JP2014210715A - Aminohydroxybenzophenone derivative, method for producing the same and ultraviolet absorber and skin external preparation using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new hydrophilic and neutral compound having ultraviolet A wave (UVA) absorbing properties and a method for producing the same, and to provide an ultraviolet absorber and a skin external preparation using the same.SOLUTION: There is provided an aminohydroxybenzophenone derivative represented by the general formula (I) and a salt thereof. (In which, Rand Reach independently represents a straight chain or branched alkyl group having 1 to 4 carbon atoms which is substituted by at least one hydroxyl group or the like; x represents COORor the like; Rrepresents a straight chain or branched alkyl group having 1 to 4 carbon atoms which is substituted by at least one hydroxyl group or the like; and Rand Reach independently represents a straight chain or branched alkyl group having 1 to 4 carbon atoms or the like.)

Description

  The present invention relates to a novel aminohydroxybenzophenone derivative having hydrophilic and neutral ultraviolet A wave (UVA) absorption action, a method for producing the same, and an ultraviolet absorbent and an external preparation for skin using the same.

  There are UV-A (320 to 400 nm) and UV-B (290 to 320 nm) as ultraviolet rays reaching the ground surface. Among them, UV-A is known to cause erythema in the skin when excessively exposed, to cause an acute inflammatory reaction and blackening, and to be one of the causes of skin cancer. Moreover, although UV-A is weak in causing erythema, it has been clarified that oxidized melanin of the skin is oxidized to cause melanin pigmentation and blackening, and causes long-term skin aging by long-term exposure. Further, ultraviolet rays also have harmful points such as various synthetic resins such as polyethylene, polypropylene, PVC, and ABS resin, and causes deterioration of paints.

  Thus, as the influence of ultraviolet rays on the skin and the like becomes clear, there is an increasing demand for sunscreen cosmetics having a high ultraviolet blocking effect. Usually, an ultraviolet scattering agent and an ultraviolet absorber are used in sunscreen cosmetics in order to block ultraviolet irradiation to the skin.

  The ultraviolet scattering agent is a material that blocks ultraviolet rays by scattering ultraviolet rays, and conventionally inorganic pigments such as zinc oxide, titanium oxide, kaolin, and calcium carbonate have been used. These can shield ultraviolet rays over a wide band, and are inactive, so that they have high skin safety and are more useful ultraviolet shielding agents.

  However, although these inorganic pigments, particularly titanium oxide and zinc oxide, have a high ultraviolet shielding effect as described above, they also have a large covering power (hiding power), so when applied to the skin, the cosmetic film becomes white and causes whitening. Become. For this reason, it has been proposed to use finely divided titanium oxide or zinc oxide (see, for example, Patent Documents 1 to 3). It is known that the finer these particles are, the higher the ultraviolet ray shielding effect is, and the higher the light transmittance in the visible light part, and thus the higher the transparency.

  However, the fine particles of these inorganic pigments generally have high cohesive properties, and it is difficult to stably disperse them in a fine particle state in a blending system such as cosmetics. For this reason, the UV shielding effect and transparency are not obtained as expected. In addition, since these fine pigments have a high light refractive index, when they are used in a large amount, the concealing property becomes high, and white floatation or the like also occurs, resulting in an unnatural cosmetic finish. Furthermore, the aggregation of the particles hinders the spreadability of the cosmetic and causes problems in use such as a squeaky feeling when applied to the skin. For this reason, the amount of these ultraviolet scattering agents is naturally limited, and a cosmetic having a desired ultraviolet shielding effect has not been obtained.

  On the other hand, ultraviolet absorbers block ultraviolet rays by absorbing light energy, but generally the absorption band of ultraviolet absorbers is present in the 280 to 350 nm region, so that it is not always sufficient to prevent broadband ultraviolet rays. I can't say that.

  In addition, conventional lipophilic UV absorbers used for sunscreen, etc. have the property (lipophilic) that does not fall off even when water touches the skin, and is basically dedicated to remove from the skin. Was needed. In recent years, sunscreens have come to be used in daily life as skin damage caused by ultraviolet rays becomes clear, and it has been demanded that sunscreens be easily washed with water. Furthermore, the increase in the amount of the lipophilic compound causes problems such as solubility in cosmetics and stability especially in aqueous solvents.

Japanese Examined Patent Publication No. 47-42502 Japanese Patent Laid-Open No. 49-00450 Japanese Patent Application Laid-Open No. 64-07941 Japanese Patent Laid-Open No. 2-111760 Japanese Patent No. 3497246 Japanese Patent No. 4705220

  In light of such circumstances, the present invention provides an aminohydroxybenzophenone derivative and a salt thereof, which are neutral hydrophilic new compounds having ultraviolet A wave (UVA) absorption action and safe for skin, and a method for producing the same. The purpose is to provide.

  The present invention also provides a neutral ultraviolet absorbent and an external preparation for skin, which have the ultraviolet A wave (UVA) absorption action and contain the aminohydroxybenzophenone derivative and salts thereof, and are safe for the skin. With the goal.

  As a result of intensive studies to solve the above problems, the present inventors have succeeded in creating a novel aminohydroxybenzophenone derivative or a salt thereof shown below, and found that the above object can be achieved by the above compound, thereby completing the present invention. It came to do.

（式中、不定項目は、互いに独立に以下の意味を有する。
Ｒ^１およびＲ^２は、それぞれ独立して、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖もしくは分岐のアルキル基、または、−（Ｒ^８−Ｏ）_ｐ−Ｒ^９を表し（ただし、Ｒ^１またはＲ^２の１つが水素原子または炭素数１〜４の直鎖もしくは分岐のアルキル基であってもよい）、また、ＮＲ^１Ｒ^２は、５または６員のヘテロ環を形成していてもよく、該ヘテロ環は少なくとも１つのヒドロキシル基で置換されており、該ヘテロ環はさらに置換されていてもよい。
Ｒ^８は、炭素数１〜４の直鎖もしくは分岐のアルキレン基を表し、Ｒ^９は、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖または分岐のアルキル基を表し、ｐは、１〜４の整数であり、ｐが２以上の場合には、複数存在するＲ^８は同一でも異なっていてもよい。
Ｘは、ＣＯＯＲ^３またはＣＯＮＲ^４Ｒ^５を表し、Ｒ^３は、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖もしくは分岐のアルキル基、または、−（Ｒ^１０−Ｏ）_ｑ−Ｒ^１１を表し、Ｒ^４およびＲ^５は、それぞれ独立して、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖もしくは分岐のアルキル基、または、−（Ｒ^１２−Ｏ）_ｒ−Ｒ^１３を表し（ただし、Ｒ^４またはＲ^５の１つが水素原子または炭素数１〜４の直鎖もしくは分岐のアルキル基であってもよい）、また、ＮＲ^４Ｒ^５は、５または６員のヘテロ環を形成していてもよく、該ヘテロ環は少なくとも１つのヒドロキシル基で置換されており、該ヘテロ環はさらに置換されていてもよい。
Ｒ^１０は、炭素数１〜４の直鎖もしくは分岐のアルキレン基を表し、Ｒ^１１は、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖または分岐のアルキル基を表し、ｑは、１〜４の整数であり、ｑが２以上の場合には、複数存在するＲ^１０は同一でも異なっていてもよい。
Ｒ^１２は、炭素数１〜４の直鎖もしくは分岐のアルキレン基を表し、Ｒ^１３は、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖または分岐のアルキル基を表し、ｒは、１〜４の整数であり、ｒが２以上の場合には、複数存在するＲ^１２は同一でも異なっていてもよい。
Ｒ^６およびＲ^７は、それぞれ独立して、炭素数１〜４の直鎖もしくは分岐のアルキル基、または、ヒドロキシル基で置換された炭素数１〜４の直鎖もしくは分岐のアルキル基を表し、ｍは、０〜３の整数であり、ｎは、０〜４の整数であり、ｍとｎはそれぞれ独立しており、ｍが２以上の場合には、複数存在するＲ^６は同一でも異なっていてもよく、ｎが２以上の場合には、複数存在するＲ^７は同一でも異なっていてもよい。） That is, the aminohydroxybenzophenone derivative or salt thereof of the present invention is represented by the general formula (I).

(In the formula, indefinite items have the following meanings independently of each other.
R ¹ and R ² each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ⁸ —O) _p —R ⁹ . (However, ^one of R ¹ or R ² may be a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), and NR ¹ R ² represents a 5- or 6-membered heterocycle. May be formed, the heterocycle is substituted with at least one hydroxyl group, and the heterocycle may be further substituted.
R ⁸ represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ⁹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, p Is an integer of 1 to 4, and when p is 2 or more, a plurality of R ⁸ may be the same or different.
X represents COOR ³ or CONR ⁴ R ⁵ , wherein R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ¹⁰ —O) _q represents -R ^{11, R 4} and ^{R 5} are each independently at least one linear or branched alkyl group having 1 to 4 carbon atoms which is substituted with a hydroxyl group ^{or,, - (R} 12 -O) _r— R ¹³ (wherein one of R ^{4 and} R ⁵ may be a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), and NR ⁴ R ⁵ is 5 or It may form a 6-membered heterocycle, and the heterocycle is substituted with at least one hydroxyl group, and the heterocycle may be further substituted.
R ¹⁰ represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ¹¹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, q Is an integer of 1 to 4, and when q is 2 or more, a plurality of R ¹⁰ may be the same or different.
R ¹² represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ¹³ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, and r Is an integer of 1 to 4, and when r is 2 or more, a plurality of R ¹² may be the same or different.
R ⁶ and R ⁷ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a hydroxyl group, m is an integer of 0 to 3, n is an integer of 0 to 4, m and n are independent of each other, and when m is 2 or more, a plurality of R ⁶ are the same or different. And when n is 2 or more, a plurality of R ⁷ may be the same or different. )

  According to the aminohydroxybenzophenone derivative or a salt thereof of the present invention, it has a structure represented by the above general formula (I), and therefore has a strong ultraviolet absorption characteristic of 320 to 400 nm and an excellent ultraviolet A wave (UVA) absorption action. It will be.

  Furthermore, according to the aminohydroxybenzophenone derivative or a salt thereof of the present invention, since it has a structure represented by the above general formula (I), it is excellent in hydrophilicity and is concerned about safety to the skin such as a sulfonic acid group. Is almost neutral (approximately in the range of about pH 5-9).

In the aminohydroxybenzophenone derivative or a salt thereof, at least one of R ¹ and R ² is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, and X is COOR ³ and R ³ is preferably — (R ¹⁰ —O) _q —R ¹¹ . In this case, the aminohydroxybenzophenone ester derivative (or salt thereof) corresponds to the aminohydroxybenzophenone ester derivative (or salt thereof), but has an ultraviolet A wave (UVA) absorption action, hydrophilicity and skin safety. Will be better.

In the aminohydroxybenzophenone derivative, at least one of R ¹ and R ² is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, and X is CONR ⁴ R ⁵ , and at least one of R ⁴ and R ⁵ is preferably a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group. In this case, it is an aminohydroxybenzophenonamide derivative (or a salt thereof), but the aminohydroxybenzophenonamide derivative (or a salt thereof) having the above structure has an ultraviolet A wave (UVA) absorption action, hydrophilicity and skin safety. It will be excellent. Furthermore, the aminohydroxybenzophenone amide derivative (or salt thereof) can also be used as a useful precursor when synthesizing the aminohydroxybenzophenone ester derivative (or salt thereof).

一般式（ＩＩ）で表される化合物またはその塩と、

（式中、不定項目は、互いに独立に以下の意味を有する。
Ｙは、フッ素、塩素、臭素、ヨウ素、または、メタンスルホニル基、ｐ−トルエンスルホニル基、ニトロベンゼンスルホニル基、トリフルオロメタンスルホニル基などのスルホン酸エステル基を表す。
Ｒ^１４は、−Ｏ−Ｒ^１５、塩素、臭素、または、ヨウ素を表し、Ｒ^１５は、炭素数１〜４の直鎖、または、分岐のアルキル基を表す。
Ｒ^６およびＲ^７は、それぞれ独立して、炭素数１〜４の直鎖もしくは分岐のアルキル基、または、ヒドロキシル基で置換された炭素数１〜４の直鎖もしくは分岐のアルキル基を表し、ｍは、０〜３の整数であり、ｎは、０〜４の整数であり、ｍとｎはそれぞれ独立しており、ｍが２以上の場合には、複数存在するＲ^６は同一でも異なっていてもよく、ｎが２以上の場合には、複数存在するＲ^７は同一でも異なっていてもよい。）
一般式（ＩＩＩ）で表される化合物またはその塩とを反応させることを特徴とする。

（式中、不定項目は、互いに独立に以下の意味を有する。
Ｒ^１およびＲ^２は、それぞれ独立して、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖もしくは分岐のアルキル基、または、−（Ｒ^８−Ｏ）_ｐ−Ｒ^９を表し（ただし、Ｒ^１またはＲ^２の１つが水素原子または炭素数１〜４の直鎖もしくは分岐のアルキル基であってもよい）、また、ＮＲ^１Ｒ^２は、５または６員のヘテロ環を形成していてもよく、該ヘテロ環は少なくとも１つのヒドロキシル基で置換されており、該ヘテロ環はさらに置換されていてもよい。
Ｒ^８は、炭素数１〜４の直鎖もしくは分岐のアルキレン基を表し、Ｒ^９は、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖または分岐のアルキル基を表し、ｐは、１〜４の整数であり、ｐが２以上の場合には、複数存在するＲ^８は同一でも異なっていてもよい。）。 In addition, the method for producing an aminohydroxybenzophenonamide derivative represented by the general formula (IV) of the present invention or a salt thereof,

A compound represented by the general formula (II) or a salt thereof;

(In the formula, indefinite items have the following meanings independently of each other.
Y represents fluorine, chlorine, bromine, iodine, or a sulfonic acid ester group such as a methanesulfonyl group, a p-toluenesulfonyl group, a nitrobenzenesulfonyl group, and a trifluoromethanesulfonyl group.
R ¹⁴ represents —O—R ¹⁵ , chlorine, bromine, or iodine, and R ¹⁵ represents a linear or branched alkyl group having 1 to 4 carbon atoms.
R ⁶ and R ⁷ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a hydroxyl group, m is an integer of 0 to 3, n is an integer of 0 to 4, m and n are independent of each other, and when m is 2 or more, a plurality of R ⁶ are the same or different. And when n is 2 or more, a plurality of R ⁷ may be the same or different. )
It is characterized by reacting a compound represented by the general formula (III) or a salt thereof.

(In the formula, indefinite items have the following meanings independently of each other.
R ¹ and R ² each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ⁸ —O) _p —R ⁹ . (However, ^one of R ¹ or R ² may be a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), and NR ¹ R ² represents a 5- or 6-membered heterocycle. May be formed, the heterocycle is substituted with at least one hydroxyl group, and the heterocycle may be further substituted.
R ⁸ represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ⁹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, p Is an integer of 1 to 4, and when p is 2 or more, a plurality of R ⁸ may be the same or different. ).

  According to the method for producing an aminohydroxybenzophenonamide derivative represented by the general formula (IV) or a salt thereof according to the present invention, the compound represented by the above general formula (II) (or a salt thereof) and the general formula (III) By reacting the represented compound (or a salt thereof), an aminohydroxybenzophenone amide derivative (or a salt thereof) can be easily obtained in a high yield. Furthermore, the aminohydroxybenzophenone amide derivative (or salt thereof) can also be used as a useful precursor when synthesizing the aminohydroxybenzophenone ester derivative (or salt thereof).

In the method for producing an aminohydroxybenzophenonamide derivative or a salt thereof, Y is fluorine, chlorine, bromine, or iodine, R ¹⁴ represents —O—R ¹⁵ , and R ¹⁵ represents carbon number 1 -4 linear or branched alkyl groups, wherein at least one of R ¹ and R ² is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group preferable. Amination on the aromatic ring of the aminohydroxybenzophenone structure by using the compound (or salt thereof) represented by the general formula (II) and the compound (or salt thereof) represented by the general formula (III) having the above structure In addition, amidation of substituents can be carried out more easily and in high yield.

一般式（ＩＶ）で表されるアミノヒドロキシベンゾフェノンアミド誘導体またはその塩と、

（式中、不定項目は、互いに独立に以下の意味を有する。
Ｒ^１およびＲ^２は、それぞれ独立して、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖もしくは分岐のアルキル基、または、−（Ｒ^８−Ｏ）_ｐ−Ｒ^９を表し（ただし、Ｒ^１またはＲ^２の１つが水素原子または炭素数１〜４の直鎖もしくは分岐のアルキル基であってもよい）、また、ＮＲ^１Ｒ^２は、５または６員のヘテロ環を形成していてもよく、該ヘテロ環は少なくとも１つのヒドロキシル基で置換されており、該ヘテロ環はさらに置換されていてもよい。
Ｒ^８は、炭素数１〜４の直鎖もしくは分岐のアルキレン基を表し、Ｒ^９は、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖または分岐のアルキル基を表し、ｐは、１〜４の整数であり、ｐが２以上の場合には、複数存在するＲ^８は同一でも異なっていてもよい。）
一般式（Ｖ）で表される化合物またはその塩とを反応させることを特徴とする。

（式中、不定項目は、互いに独立に以下の意味を有する。
Ｒ^３は、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖もしくは分岐のアルキル基、または、−（Ｒ^１０−Ｏ）_ｑ−Ｒ^１１を表す。
Ｒ^１０は、炭素数１〜４の直鎖もしくは分岐のアルキレン基を表し、Ｒ^１１は、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖または分岐のアルキル基を表し、ｑは、１〜４の整数であり、ｑが２以上の場合には、複数存在するＲ^１０は同一でも異なっていてもよい。）。 In addition, a method for producing an aminohydroxybenzophenone ester derivative represented by the general formula (VI) of the present invention or a salt thereof,

An aminohydroxybenzophenone amide derivative represented by the general formula (IV) or a salt thereof;

(In the formula, indefinite items have the following meanings independently of each other.
R ¹ and R ² each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ⁸ —O) _p —R ⁹ . (However, ^one of R ¹ or R ² may be a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), and NR ¹ R ² represents a 5- or 6-membered heterocycle. May be formed, the heterocycle is substituted with at least one hydroxyl group, and the heterocycle may be further substituted.
R ⁸ represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ⁹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, p Is an integer of 1 to 4, and when p is 2 or more, a plurality of R ⁸ may be the same or different. )
It is characterized by reacting the compound represented by the general formula (V) or a salt thereof.

(In the formula, indefinite items have the following meanings independently of each other.
R ³ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ¹⁰ —O) _q —R ¹¹ .
R ¹⁰ represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ¹¹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, q Is an integer of 1 to 4, and when q is 2 or more, a plurality of R ¹⁰ may be the same or different. ).

  According to the method for producing an aminohydroxybenzophenone ester derivative represented by the general formula (VI) or a salt thereof according to the present invention, the compound represented by the general formula (IV) (or a salt thereof) and the general formula (V) By reacting the represented compound (or a salt thereof), an aminohydroxybenzophenone ester derivative (or a salt thereof) can be easily obtained in a high yield. Furthermore, the aminohydroxybenzophenone amide derivative (and salt thereof) can be used as the aminohydroxybenzophenone ester derivative (or salt thereof).

In the method for producing the aminohydroxybenzophenone ester derivative and the salt thereof, at least one of R ¹ and R ² is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group. R ³ is preferably — (R ¹⁰ —O) _q —R ¹¹ . By using the compound (or salt thereof) represented by the general formula (VI) and the compound (or salt thereof) represented by the general formula (V) having the above structure, an amide ester of a substituent having an aminohydroxybenzophenone structure The substitution reaction can be performed more easily and in high yield.

  Moreover, the ultraviolet absorber of this invention is characterized by including the said aminohydroxybenzophenone derivative or its salt. According to the ultraviolet absorber of the present invention, since the aminohydroxybenzophenone derivative or its salt having the above-described effects is used, it can be easily formulated particularly as a water-soluble composition, and has an ultraviolet A wave (UVA) absorption action. A neutral UV absorber that is hydrophilic and safe for the skin can be obtained.

  Moreover, the skin external preparation of this invention is characterized by including the said aminohydroxybenzophenone derivative or its salt. According to the external preparation for skin of the present invention, since the aminohydroxybenzophenone derivative or salt thereof having the above-described effects is used, it can be easily molded and formulated as a water-soluble agent, and absorbs ultraviolet A wave (UVA). It is possible to obtain a neutral skin external preparation having an action, which is hydrophilic and safe for the skin.

  The aminohydroxybenzophenone derivative or salt thereof of the present invention is a novel compound, has hydrophilicity, is neutral and safe for the skin, and has an excellent ultraviolet A wave (UVA) absorption action.

  Further, by using the method for producing an aminohydroxybenzophenone amide derivative or a salt thereof of the present invention, an aminohydroxybenzophenone amide derivative (or a salt thereof), which is a novel compound, can be easily obtained in a high yield. Further, by using the method for producing an aminohydroxybenzophenone ester derivative or a salt thereof of the present invention, an aminohydroxybenzophenone ester derivative (or a salt thereof) can be easily obtained at a high yield.

  Further, since the ultraviolet absorbent and the external preparation for skin of the present invention contain the above novel aminohydroxybenzophenone derivative or a salt thereof, it has hydrophilicity, is neutral and safe for the skin, and has excellent ultraviolet A wave ( It has a UVA) absorption action and is useful as an ultraviolet absorber and a skin external preparation.

  Hereinafter, embodiments of the present invention will be described in detail.

（式中、不定項目は、互いに独立に以下の意味を有する。
Ｒ^１およびＲ^２は、それぞれ独立して、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖もしくは分岐のアルキル基、または、−（Ｒ^８−Ｏ）_ｐ−Ｒ^９を表し（ただし、Ｒ^１またはＲ^２の１つが水素原子または炭素数１〜４の直鎖もしくは分岐のアルキル基であってもよい）、また、ＮＲ^１Ｒ^２は、５または６員のヘテロ環を形成していてもよく、該ヘテロ環は少なくとも１つのヒドロキシル基で置換されており、該ヘテロ環はさらに置換されていてもよい。
Ｒ^８は、炭素数１〜４の直鎖もしくは分岐のアルキレン基を表し、Ｒ^９は、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖または分岐のアルキル基を表し、ｐは、１〜４の整数であり、ｐが２以上の場合には、複数存在するＲ^８は同一でも異なっていてもよい。
Ｘは、ＣＯＯＲ^３またはＣＯＮＲ^４Ｒ^５を表し、Ｒ^３は、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖もしくは分岐のアルキル基、または、−（Ｒ^１０−Ｏ）_ｑ−Ｒ^１１を表し、Ｒ^４およびＲ^５は、それぞれ独立して、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖もしくは分岐のアルキル基、または、−（Ｒ^１２−Ｏ）_ｒ−Ｒ^１３を表し（ただし、Ｒ^４またはＲ^５の１つが水素原子または炭素数１〜４の直鎖もしくは分岐のアルキル基であってもよい）、また、ＮＲ^４Ｒ^５は、５または６員のヘテロ環を形成していてもよく、該ヘテロ環は少なくとも１つのヒドロキシル基で置換されており、該ヘテロ環はさらに置換されていてもよい。
Ｒ^１０は、炭素数１〜４の直鎖もしくは分岐のアルキレン基を表し、Ｒ^１１は、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖または分岐のアルキル基を表し、ｑは、１〜４の整数であり、ｑが２以上の場合には、複数存在するＲ^１０は同一でも異なっていてもよい。
Ｒ^１２は、炭素数１〜４の直鎖もしくは分岐のアルキレン基を表し、Ｒ^１３は、少なくとも１つのヒドロキシル基で置換された炭素数１〜４の直鎖または分岐のアルキル基を表し、ｒは、１〜４の整数であり、ｒが２以上の場合には、複数存在するＲ^１２は同一でも異なっていてもよい。
Ｒ^６およびＲ^７は、それぞれ独立して、炭素数１〜４の直鎖もしくは分岐のアルキル基、または、ヒドロキシル基で置換された炭素数１〜４の直鎖もしくは分岐のアルキル基を表し、ｍは、０〜３の整数であり、ｎは、０〜４の整数であり、ｍとｎはそれぞれ独立しており、ｍが２以上の場合には、複数存在するＲ^６は同一でも異なっていてもよく、ｎが２以上の場合には、複数存在するＲ^７は同一でも異なっていてもよい。） [Aminohydroxybenzophenone derivative or salt thereof]
The aminohydroxybenzophenone derivative or a salt thereof of the present invention is represented by the general formula (I).

(In the formula, indefinite items have the following meanings independently of each other.
R ¹ and R ² each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ⁸ —O) _p —R ⁹ . (However, ^one of R ¹ or R ² may be a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), and NR ¹ R ² represents a 5- or 6-membered heterocycle. May be formed, the heterocycle is substituted with at least one hydroxyl group, and the heterocycle may be further substituted.
R ⁸ represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ⁹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, p Is an integer of 1 to 4, and when p is 2 or more, a plurality of R ⁸ may be the same or different.
X represents COOR ³ or CONR ⁴ R ⁵ , wherein R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ¹⁰ —O) _q represents -R ^{11, R 4} and ^{R 5} are each independently at least one linear or branched alkyl group having 1 to 4 carbon atoms which is substituted with a hydroxyl group ^{or,, - (R} 12 -O) _r— R ¹³ (wherein one of R ^{4 and} R ⁵ may be a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), and NR ⁴ R ⁵ is 5 or It may form a 6-membered heterocycle, and the heterocycle is substituted with at least one hydroxyl group, and the heterocycle may be further substituted.
R ¹⁰ represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ¹¹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, q Is an integer of 1 to 4, and when q is 2 or more, a plurality of R ¹⁰ may be the same or different.
R ¹² represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ¹³ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, and r Is an integer of 1 to 4, and when r is 2 or more, a plurality of R ¹² may be the same or different.
R ⁶ and R ⁷ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a hydroxyl group, m is an integer of 0 to 3, n is an integer of 0 to 4, m and n are independent of each other, and when m is 2 or more, a plurality of R ⁶ are the same or different. And when n is 2 or more, a plurality of R ⁷ may be the same or different. )

In the general formula (I), R ¹ and R ² each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ⁸ — _O) represents the p -R ^9. One of R ¹ or R ² may be a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. NR ¹ R ² may form a 5- or 6-membered heterocycle, and the heterocycle is substituted with at least one hydroxyl group, and the heterocycle may be further substituted.

Examples of the linear or branched alkyl group having 1 to 4 carbon atoms substituted with the hydroxyl group in R ¹ and R ² include, for example, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, 2, 2-dihydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,2-dihydroxypropyl group, 1,3-dihydroxypropyl group, 2,3-dihydroxypropyl group, 1, 1-dihydroxypropyl group, 2,2-dihydroxypropyl group, 3,3-dihydroxypropyl group, 1-methyl-1-hydroxyethyl group, 1-methyl-2-hydroxyethyl group, 1,1-dimethyl-1- Hydroxymethyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybuty Group, 4-hydroxybutyl group, 1,2-dihydroxybutyl group, 1,3-dihydroxybutyl group, 1,4-dihydroxybutyl group, 2,3-dihydroxybutyl group, 2,4-dihydroxybutyl group, 1, 1-dihydroxybutyl group, 2,2-dihydroxybutyl group, 3,3-dihydroxybutyl group, 1-hydroxy-1-methylpropyl group, 2-hydroxy-1-methylpropyl group, 3-hydroxy-1-methylpropyl Group, 1-hydroxymethylpropyl group, 1,1-dimethyl-2-hydroxyethyl group, 2-methyl-1-hydroxypropyl group, 2-methyl-2-hydroxypropyl group, 2-methyl-3-hydroxypropyl group Etc. From the viewpoint that a higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the number of carbon atoms of the alkyl group is an integer of 1 to 2 (that is, a hydroxymethyl group, a 1-hydroxyethyl group, or 2-hydroxyethyl group) is preferred.

Examples of the linear or branched alkyl group having 1 to 4 carbon atoms in R ¹ or R ² include a methyl group, an ethyl group, a 1-propyl group, a 1-methyl-1-ethyl group, and a 1-butyl group. 1-methyl-1-propyl group, 1,1-dimethyl-1-ethyl group, 2-methyl-1-propyl group, and the like. From the viewpoint that higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the alkyl group preferably has an integer of 1 to 2 (that is, a methyl group or an ethyl group).

R ⁸ represents a linear or branched alkylene group having 1 to 4 carbon atoms. Examples of the linear or branched alkylene group having 1 to 4 carbon atoms include methylene group, ethylene group, 1-propylene group, 1-methyl-1-ethylene group, 1-butylene group, and 1-methyl-1-propylene. Group, 1,1-dimethyl-1-ethylene group, 2-methyl-1-propylene group and the like. From the viewpoint that a higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the alkylene group preferably has an integer of 1 to 2 (that is, a methylene group or an ethylene group).

R ⁹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group. Examples of the linear or branched alkyl group having 1 to 4 carbon atoms substituted with the hydroxyl group include, for example, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 2,2-dihydroxyethyl group, 1- Hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,2-dihydroxypropyl group, 1,3-dihydroxypropyl group, 2,3-dihydroxypropyl group, 1,1-dihydroxypropyl group, 2, 2-dihydroxypropyl group, 3,3-dihydroxypropyl group, 1-methyl-1-hydroxyethyl group, 1-methyl-2-hydroxyethyl group, 1,1-dimethyl-1-hydroxymethyl group, 1-hydroxybutyl Group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 1,2-dihydroxybutyl group, 1,3-dihydroxybutyl group, 1,4-dihydroxybutyl group, 2,3-dihydroxybutyl group, 2,4-dihydroxybutyl group, 1,1-dihydroxybutyl group, 2, 2-dihydroxybutyl group, 3,3-dihydroxybutyl group, 1-hydroxy-1-methylpropyl group, 2-hydroxy-1-methylpropyl group, 3-hydroxy-1-methylpropyl group, 1-hydroxymethylpropyl group 1,1-dimethyl-2-hydroxyethyl group, 2-methyl-1-hydroxypropyl group, 2-methyl-2-hydroxypropyl group, 2-methyl-3-hydroxypropyl group, and the like. From the viewpoint that higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the alkyl group preferably has an integer of 1 to 2 (that is, a methyl group or an ethyl group).

The above p is an integer of 1 to 4, and when p is 2 or more, a plurality of R ⁸ may be the same or different. From the viewpoint of exhibiting higher absorbance (absorbance of ultraviolet rays per mass) and being able to be produced from a general-purpose reagent raw material, the p is preferably an integer of 1 to 2, and more preferably 1. .

Examples of — (R ⁸ —O) _p —R ⁹ include — (CH ₂ O) —CH ₂ OH, — (CH ₂ O) —C ₂ H ₄ OH, — (CH ₂ O) ₂ —CH _{2. OH, - (CH 2 O)} 2 -C 2 H 4 OH, - (C 2 H 4 O) -CH 2 OH, - (C 2 H 4 O) -C 2 H 4 OH, - (C 2 H 4 _{O) 2 -CH 2 OH, -} (C 2 H 4 O) 2 -C 2 H 4 OH, - (CH 2 O) 3 -CH 2 OH, - (C 2 H 4 O) 3 -C 2 H 4 _{OH, - (CH 2 O)} 4 -CH 2 OH, - (C 2 H 4 O) such as ₄ -C _{2 H 4} OH and the like.

When the NR ¹ R ² forms a 5- or 6-membered heterocycle, examples of the NR ¹ R ² include a 2-hydroxy-1-pyrrolidinyl group, a 3-hydroxy-1-pyrrolidinyl group, and 2,3-dihydroxy- 1-pyrrolidinyl group, 2-hydroxy-3-methyl-1-pyrrolidinyl group, 3-hydroxy-2-methyl-1-pyrrolidinyl group, 2-hydroxy-3-ethyl-1-pyrrolidinyl group, 3-hydroxy-2- Ethyl-1-pyrrolidinyl group, 2,4-dihydroxy-3-methyl-1-pyrrolidinyl group, 2,3-dihydroxy-2-methyl-1-pyrrolidinyl group, 2,4-hydroxy-3-ethyl-1-pyrrolidinyl group Group, 2,3-hydroxy-2-ethyl-1-pyrrolidinyl group, 2-hydroxy-1-piperidinyl group, 3-hydroxy-1-piperyl group Nyl group, 4-hydroxy-1-pyrrolidinyl group, 2,3-dihydroxy-1-piperidinyl group, 2-hydroxy-3-methyl-1-piperidinyl group, 3-hydroxy-2-methyl-1-piperidinyl group, 4 -Hydroxy-2-methyl-1-piperidinyl group, 4-hydroxy-3-methyl-1-piperidinyl group, 2,4-dihydroxy-3-methyl-1-piperidinyl group, 2,5-dihydroxy-3-methyl- 1-piperidinyl group, 3,4-dihydroxy-2-methyl-1-piperidinyl group, 3,5-dihydroxy-2-methyl-1-piperidinyl group, 3,4-hydroxy-2-methyl-1-piperidinyl group, 2-hydroxymethyl-1-pyrrolidinyl group, 3-hydroxymethyl-1-pyrrolidinyl group, 2,3-di (hydroxymethyl) -1 Pyrrolidinyl group, 2-hydroxymethyl-3-methyl-1-pyrrolidinyl group, 3-hydroxymethyl-2-methyl-1-pyrrolidinyl group, 2-hydroxyethyl-1-pyrrolidinyl group, 3-hydroxyethyl-1-pyrrolidinyl group 2-hydroxyethyl-3-methyl-1-pyrrolidinyl group, 3-hydroxyethyl-2-methyl-1-pyrrolidinyl group, 2-hydroxymethyl-1-piperidinyl group, 3-hydroxymethyl-1-piperidinyl group, 4 -Hydroxymethyl-1-piperidinyl group, 2,3-dihydroxymethyl-1-piperidinyl group, 2,4-dihydroxymethyl-1-piperidinyl group, 3,4-dihydroxymethyl-1-piperidinyl group, 2-hydroxymethyl- 3-methyl-1-piperidinyl group, 3-hydroxymethyl-2- Methyl-1-piperidinyl group, 4-hydroxymethyl-2-methyl-1-piperidinyl group, 4-hydroxymethyl-3-methyl-1-piperidinyl group, 2-hydroxyethyl-1-piperidinyl group, 3-hydroxyethyl- 1-piperidinyl group, 4-hydroxyethyl-1-piperidinyl group, 2-hydroxyethyl-3-methyl-1-piperidinyl group, 3-hydroxyethyl-2-methyl-1-piperidinyl group, 4-hydroxyethyl-2- Examples thereof include a methyl-1-piperidinyl group and 4-hydroxyethyl-3-methyl-1-piperidinyl group.

  In addition, the heterocycle may be further substituted. Examples of the substituent when substituted include a methyl group, an ethyl group, an n-propyl group, a 1-methylethyl group (i-propyl group), a 1-butyl group (n-butyl group), and a 1-methylpropyl group. (I-butyl group), 2-methylpropyl group (s-butyl), 1,1-dimethylethyl group (t-butyl group) and other alkyl groups, hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, etc. be able to. From the viewpoint that higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the alkyl group preferably has an integer of 1 to 2 (that is, a methyl group or an ethyl group).

R ⁶ and R ⁷ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a hydroxyl group. . Examples of the linear or branched alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a 1-propyl group, a 1-methyl-1-ethyl group, a 1-butyl group, and a 1-methyl-1-propyl group. Group, 1,1-dimethyl-1-ethyl group, 2-methyl-1-propyl group and the like. Examples of the linear or branched alkyl group having 1 to 4 carbon atoms substituted with the hydroxyl group include, for example, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 2,2-dihydroxyethyl group, 1- Hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,2-dihydroxypropyl group, 1,3-dihydroxypropyl group, 2,3-dihydroxypropyl group, 1,1-dihydroxypropyl group, 2, 2-dihydroxypropyl group, 3,3-dihydroxypropyl group, 1-methyl-1-hydroxyethyl group, 1-methyl-2-hydroxyethyl group, 1,1-dimethyl-1-hydroxymethyl group, 1-hydroxybutyl Group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 1,2-dihydroxybutyl group, 1,3-dihydroxybutyl group, 1,4-dihydroxybutyl group, 2,3-dihydroxybutyl group, 2,4-dihydroxybutyl group, 1,1-dihydroxybutyl group, 2, 2-dihydroxybutyl group, 3,3-dihydroxybutyl group, 1-hydroxy-1-methylpropyl group, 2-hydroxy-1-methylpropyl group, 3-hydroxy-1-methylpropyl group, 1-hydroxymethylpropyl group 1,1-dimethyl-2-hydroxyethyl group, 2-methyl-1-hydroxypropyl group, 2-methyl-2-hydroxypropyl group, 2-methyl-3-hydroxypropyl group, and the like. From the viewpoint that higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the alkyl group preferably has an integer of 1 to 2 (that is, a methyl group or an ethyl group).

The m is an integer from 0 to 3, the n is an integer from 0 to 4, and m and n are independent of each other. When m is 2 or more, a plurality of R ⁶ may be the same or different. When n is 2 or more, a plurality of R ⁷ may be the same or different.

In the above general formula (I), X represents COOR ³ or CONR ⁴ R ⁵ , and R ³ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or - represents _{^{(R 10 -O) q -R 11}} , R 4 and ^{R 5} are each independently at least one linear or branched alkyl group having 1 to 4 carbon atoms which is substituted with a hydroxyl group or, , ^- represents the ^{_{(R 12 -O) r -R 13}} . One of R ^{4 and} R ⁵ may be a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. NR ⁴ R ⁵ may form a 5- or 6-membered heterocycle, and the heterocycle is substituted with at least one hydroxyl group, and the heterocycle may be further substituted.

Examples of the linear or branched alkyl group having 1 to 4 carbon atoms substituted with the at least one hydroxyl group in R ³ include, for example, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, 2, 2-dihydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,2-dihydroxypropyl group, 1,3-dihydroxypropyl group, 2,3-dihydroxypropyl group, 1, 1-dihydroxypropyl group, 2,2-dihydroxypropyl group, 3,3-dihydroxypropyl group, 1-methyl-1-hydroxyethyl group, 1-methyl-2-hydroxyethyl group, 1,1-dimethyl-1- Hydroxymethyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxy Butyl group, 4-hydroxybutyl group, 1,2-dihydroxybutyl group, 1,3-dihydroxybutyl group, 1,4-dihydroxybutyl group, 2,3-dihydroxybutyl group, 2,4-dihydroxybutyl group, 1 , 1-dihydroxybutyl group, 2,2-dihydroxybutyl group, 3,3-dihydroxybutyl group, 1-hydroxy-1-methylpropyl group, 2-hydroxy-1-methylpropyl group, 3-hydroxy-1-methyl Propyl group, 1-hydroxymethylpropyl group, 1,1-dimethyl-2-hydroxyethyl group, 2-methyl-1-hydroxypropyl group, 2-methyl-2-hydroxypropyl group, 2-methyl-3-hydroxypropyl Group.

R ¹⁰ represents a linear or branched alkylene group having 1 to 4 carbon atoms. Examples of the linear or branched alkylene group having 1 to 4 carbon atoms include methylene group, ethylene group, 1-propylene group, 1-methyl-1-ethylene group, 1-butylene group, and 1-methyl-1-propylene. Group, 1,1-dimethyl-1-ethylene group, 2-methyl-1-propylene group and the like. From the viewpoint that a higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the alkylene group preferably has an integer of 1 to 2 (that is, a methylene group or an ethylene group).

R ¹¹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group. Examples of the linear or branched alkyl group having 1 to 4 carbon atoms substituted with the hydroxyl group include, for example, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 2,2-dihydroxyethyl group, 1- Hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,2-dihydroxypropyl group, 1,3-dihydroxypropyl group, 2,3-dihydroxypropyl group, 1,1-dihydroxypropyl group, 2, 2-dihydroxypropyl group, 3,3-dihydroxypropyl group, 1-methyl-1-hydroxyethyl group, 1-methyl-2-hydroxyethyl group, 1,1-dimethyl-1-hydroxymethyl group, 1-hydroxybutyl Group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 1,2-dihydroxybutyl group, 1,3-dihydroxybutyl group, 1,4-dihydroxybutyl group, 2,3-dihydroxybutyl group, 2,4-dihydroxybutyl group, 1,1-dihydroxybutyl group, 2, 2-dihydroxybutyl group, 3,3-dihydroxybutyl group, 1-hydroxy-1-methylpropyl group, 2-hydroxy-1-methylpropyl group, 3-hydroxy-1-methylpropyl group, 1-hydroxymethylpropyl group 1,1-dimethyl-2-hydroxyethyl group, 2-methyl-1-hydroxypropyl group, 2-methyl-2-hydroxypropyl group, 2-methyl-3-hydroxypropyl group, and the like. From the viewpoint that higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the alkyl group preferably has an integer of 1 to 2 (that is, a methyl group or an ethyl group).

Q is an integer of 1 to 4, and when q is 2 or more, a plurality of R ¹⁰ may be the same or different. From the viewpoint of exhibiting higher absorbance (absorbance of ultraviolet rays per mass) and being able to be produced from a general-purpose reagent raw material, q is preferably an integer of 1 to 2, and more preferably 1. .

The ^- as ^{_{(R 10 -O) q -R 11}} , for _{example, - (CH 2 O) -CH} 2 OH, - (CH 2 O) -C 2 H 4 OH, - (CH 2 O) 2 -CH 2 _{OH, - (CH 2 O)} 2 -C 2 H 4 OH, - (C 2 H 4 O) -CH 2 OH, - (C 2 H 4 O) -C 2 H 4 OH, - (C 2 H 4 _{O) 2 -CH 2 OH, -} (C 2 H 4 O) 2 -C 2 H 4 OH, - (CH 2 O) 3 -CH 2 OH, - (C 2 H 4 O) 3 -C 2 H 4 _{OH, - (CH 2 O)} 4 -CH 2 OH, - (C 2 H 4 O) such as ₄ -C _{2 H 4} OH and the like.

Examples of the linear or branched alkyl group having 1 to 4 carbon atoms substituted with the hydroxyl group in R ⁴ and R ⁵ include, for example, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, 2, 2-dihydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,2-dihydroxypropyl group, 1,3-dihydroxypropyl group, 2,3-dihydroxypropyl group, 1, 1-dihydroxypropyl group, 2,2-dihydroxypropyl group, 3,3-dihydroxypropyl group, 1-methyl-1-hydroxyethyl group, 1-methyl-2-hydroxyethyl group, 1,1-dimethyl-1- Hydroxymethyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybuty Group, 4-hydroxybutyl group, 1,2-dihydroxybutyl group, 1,3-dihydroxybutyl group, 1,4-dihydroxybutyl group, 2,3-dihydroxybutyl group, 2,4-dihydroxybutyl group, 1, 1-dihydroxybutyl group, 2,2-dihydroxybutyl group, 3,3-dihydroxybutyl group, 1-hydroxy-1-methylpropyl group, 2-hydroxy-1-methylpropyl group, 3-hydroxy-1-methylpropyl Group, 1-hydroxymethylpropyl group, 1,1-dimethyl-2-hydroxyethyl group, 2-methyl-1-hydroxypropyl group, 2-methyl-2-hydroxypropyl group, 2-methyl-3-hydroxypropyl group Etc. From the viewpoint that a higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the number of carbon atoms of the alkyl group is an integer of 1 to 2 (that is, a hydroxymethyl group, a 1-hydroxyethyl group, or 2-hydroxyethyl group) is preferred.

Examples of the linear or branched alkyl group having 1 to 4 carbon atoms in R ⁴ or R ⁵ include a methyl group, an ethyl group, a 1-propyl group, a 1-methyl-1-ethyl group, and a 1-butyl group. 1-methyl-1-propyl group, 1,1-dimethyl-1-ethyl group, 2-methyl-1-propyl group, and the like. From the viewpoint that higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the alkyl group preferably has an integer of 1 to 2 (that is, a methyl group or an ethyl group).

R ¹² represents a linear or branched alkylene group having 1 to 4 carbon atoms. Examples of the linear or branched alkylene group having 1 to 4 carbon atoms include methylene group, ethylene group, 1-propylene group, 1-methyl-1-ethylene group, 1-butylene group, and 1-methyl-1-propylene. Group, 1,1-dimethyl-1-ethylene group, 2-methyl-1-propylene group and the like. From the viewpoint that a higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the alkylene group preferably has an integer of 1 to 2 (that is, a methylene group or an ethylene group).

R ¹³ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group. Examples of the linear or branched alkyl group having 1 to 4 carbon atoms substituted with the hydroxyl group include, for example, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 2,2-dihydroxyethyl group, 1- Hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1,2-dihydroxypropyl group, 1,3-dihydroxypropyl group, 2,3-dihydroxypropyl group, 1,1-dihydroxypropyl group, 2, 2-dihydroxypropyl group, 3,3-dihydroxypropyl group, 1-methyl-1-hydroxyethyl group, 1-methyl-2-hydroxyethyl group, 1,1-dimethyl-1-hydroxymethyl group, 1-hydroxybutyl Group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 1,2-dihydroxybutyl group, 1,3-dihydroxybutyl group, 1,4-dihydroxybutyl group, 2,3-dihydroxybutyl group, 2,4-dihydroxybutyl group, 1,1-dihydroxybutyl group, 2, 2-dihydroxybutyl group, 3,3-dihydroxybutyl group, 1-hydroxy-1-methylpropyl group, 2-hydroxy-1-methylpropyl group, 3-hydroxy-1-methylpropyl group, 1-hydroxymethylpropyl group 1,1-dimethyl-2-hydroxyethyl group, 2-methyl-1-hydroxypropyl group, 2-methyl-2-hydroxypropyl group, 2-methyl-3-hydroxypropyl group, and the like. From the viewpoint that higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the alkyl group preferably has an integer of 1 to 2 (that is, a methyl group or an ethyl group).

R is an integer of 1 to 4, and when r is 2 or more, a plurality of R ¹² may be the same or different. From the viewpoint of exhibiting higher absorbance (absorbance of ultraviolet rays per mass) and being able to be produced from general-purpose reagent raw materials, r is preferably an integer of 1 to 2, and more preferably 1. .

Examples of — (R ¹² —O) _r —R ¹³ include — (CH ₂ O) —CH ₂ OH, — (CH ₂ O) —C ₂ H ₄ OH, — (CH ₂ O) ₂ —CH _{2. OH, - (CH 2 O)} 2 -C 2 H 4 OH, - (C 2 H 4 O) -CH 2 OH, - (C 2 H 4 O) -C 2 H 4 OH, - (C 2 H 4 _{O) 2 -CH 2 OH, -} (C 2 H 4 O) 2 -C 2 H 4 OH, - (CH 2 O) 3 -CH 2 OH, - (C 2 H 4 O) 3 -C 2 H 4 _{OH, - (CH 2 O)} 4 -CH 2 OH, - (C 2 H 4 O) such as ₄ -C _{2 H 4} OH and the like.

When the NR ⁴ R ⁵ forms a 5- or 6-membered heterocycle, examples of the NR ⁴ R ⁵ include a 2-hydroxy-1-pyrrolidinyl group, a 3-hydroxy-1-pyrrolidinyl group, and a 2,3-dihydroxy- 1-pyrrolidinyl group, 2-hydroxy-3-methyl-1-pyrrolidinyl group, 3-hydroxy-2-methyl-1-pyrrolidinyl group, 2-hydroxy-3-ethyl-1-pyrrolidinyl group, 3-hydroxy-2- Ethyl-1-pyrrolidinyl group, 2,4-dihydroxy-3-methyl-1-pyrrolidinyl group, 2,3-dihydroxy-2-methyl-1-pyrrolidinyl group, 2,4-hydroxy-3-ethyl-1-pyrrolidinyl group Group, 2,3-hydroxy-2-ethyl-1-pyrrolidinyl group, 2-hydroxy-1-piperidinyl group, 3-hydroxy-1-piperyl group Nyl group, 4-hydroxy-1-pyrrolidinyl group, 2,3-dihydroxy-1-piperidinyl group, 2-hydroxy-3-methyl-1-piperidinyl group, 3-hydroxy-2-methyl-1-piperidinyl group, 4 -Hydroxy-2-methyl-1-piperidinyl group, 4-hydroxy-3-methyl-1-piperidinyl group, 2,4-dihydroxy-3-methyl-1-piperidinyl group, 2,5-dihydroxy-3-methyl- 1-piperidinyl group, 3,4-dihydroxy-2-methyl-1-piperidinyl group, 3,5-dihydroxy-2-methyl-1-piperidinyl group, 3,4-hydroxy-2-methyl-1-piperidinyl group, 2-hydroxymethyl-1-pyrrolidinyl group, 3-hydroxymethyl-1-pyrrolidinyl group, 2,3-di (hydroxymethyl) -1 Pyrrolidinyl group, 2-hydroxymethyl-3-methyl-1-pyrrolidinyl group, 3-hydroxymethyl-2-methyl-1-pyrrolidinyl group, 2-hydroxyethyl-1-pyrrolidinyl group, 3-hydroxyethyl-1-pyrrolidinyl group 2-hydroxyethyl-3-methyl-1-pyrrolidinyl group, 3-hydroxyethyl-2-methyl-1-pyrrolidinyl group, 2-hydroxymethyl-1-piperidinyl group, 3-hydroxymethyl-1-piperidinyl group, 4 -Hydroxymethyl-1-piperidinyl group, 2,3-dihydroxymethyl-1-piperidinyl group, 2,4-dihydroxymethyl-1-piperidinyl group, 3,4-dihydroxymethyl-1-piperidinyl group, 2-hydroxymethyl- 3-methyl-1-piperidinyl group, 3-hydroxymethyl-2- Methyl-1-piperidinyl group, 4-hydroxymethyl-2-methyl-1-piperidinyl group, 4-hydroxymethyl-3-methyl-1-piperidinyl group, 2-hydroxyethyl-1-piperidinyl group, 3-hydroxyethyl- 1-piperidinyl group, 4-hydroxyethyl-1-piperidinyl group, 2-hydroxyethyl-3-methyl-1-piperidinyl group, 3-hydroxyethyl-2-methyl-1-piperidinyl group, 4-hydroxyethyl-2- Examples thereof include a methyl-1-piperidinyl group and 4-hydroxyethyl-3-methyl-1-piperidinyl group.

  In addition, the heterocycle may be further substituted. Examples of the substituent when substituted include a methyl group, an ethyl group, a 1-propyl group (n-propyl group), a 1-methylethyl group (i-propyl group), and a 1-butyl group (n-butyl group). Alkyl groups such as 1-methylpropyl group (i-butyl group), 2-methylpropyl group (s-butyl), 1,1-dimethylethyl group (t-butyl group), hydroxymethyl group, hydroxyethyl group, Examples thereof include a hydroxypropyl group. From the viewpoint that higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the alkyl group preferably has an integer of 1 to 2 (that is, a methyl group or an ethyl group).

In the aminohydroxybenzophenone derivative or a salt thereof, at least one of R ¹ and R ² is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, and X is COOR ³ and R ³ is preferably — (R ¹⁰ —O) _q —R ¹¹ . In this case, it is an aminohydroxybenzophenone ester derivative (or a salt thereof), but the aminohydroxybenzophenone ester derivative (or a salt thereof) having the above structure has an ultraviolet A wave (UVA) absorption action, and has hydrophilicity and skin safety. It will be excellent.

In the aminohydroxybenzophenone derivative, at least one of R ¹ and R ² is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, and X is CONR ⁴ R ⁵ , and at least one of R ⁴ and R ⁵ is preferably a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group. In this case, the aminohydroxybenzophenonamide derivative (or salt thereof) corresponds to the aminohydroxybenzophenonamide derivative (or salt thereof). However, the aminohydroxybenzophenonamide derivative (or salt thereof) having the above structure has an ultraviolet A wave (UVA) absorption action, and is hydrophilic and safe for the skin. It will be excellent. Furthermore, the aminohydroxybenzophenone amide derivative (or salt thereof) can also be used as a useful precursor when synthesizing the aminohydroxybenzophenone ester derivative (or salt thereof).

  The aminohydroxybenzophenone derivative of the present invention has a basic nitrogen atom and can take a salt structure with an acid added. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and hydrobromic acid, or acetic acid, citric acid, gluconic acid, tartaric acid, lactic acid, maleic acid, fumaric acid, methanesulfonic acid, p -Organic acids, such as toluenesulfonic acid and nitrobenzenesulfonic acid. These acids may be used alone or in combination of two or more. The present invention also includes acid addition salts of the above aminohydroxybenzophenone derivatives.

  In addition, the aminohydroxybenzophenone derivative of the present invention has an acidic phenolic hydroxyl group, and depending on pH conditions, protons dissociate, and the generated anion (phenoxide anion) contains sodium ion, potassium ion, lithium ion, It can have a salt structure in which counter cations such as calcium ion, magnesium ion, aluminum ion, triethanolammonium ion, and diethanolammonium ion are bonded. These counter cations may be used alone or in admixture of two or more. The present invention also includes acid addition salts of the above aminohydroxybenzophenone derivatives.

The aminohydroxybenzophenone derivative or a salt thereof has an electron-donating hydroxyl group and a nitrogen atom (amino group. Furthermore, R ¹ and R ^{2 as} electron-donating groups are bonded to the amino group. In addition, the electron density on the nitrogen atom is further increased.) In addition, the adjacent benzene ring and a carboxyl group (or an amide group, etc.) on the benzene ring are bonded via a carbonyl group that is generally electron withdrawing. Thus, the conjugated system is expanded, and the absorption wavelength is shifted to the longer wavelength side. For this reason, the aminohydroxybenzophenone derivative or salt thereof of the present invention can effectively absorb ultraviolet rays on the long wavelength side, that is, ultraviolet A waves (UVA). Further, the absorbance (measured using a quartz cell having a concentration of 5 ppm and an optical path length of 1 cm) in the UVA region of the aminohydroxybenzophenone derivative or a salt thereof is usually 0.02 or more, more preferably 0.2 to 1. .

  The molecular weight of the aminohydroxybenzophenone derivative or salt thereof of the present invention is usually about 150 to 1,000, preferably 150 to 500. When the molecular weight increases, the UVA absorption capacity per unit weight tends to decrease, and it becomes necessary to add a larger amount when used as an ultraviolet absorber or a skin external preparation.

Further, the aminohydroxybenzophenone derivative or a salt thereof of the present invention is in a positional relationship in which the hydroxyl group (phenolic hydroxyl group) and carbonyl group bonded on the same benzene ring are in the ortho position in terms of chemical structure. For this reason, the aminohydroxybenzophenone derivative or a salt thereof easily forms an intramolecular hydrogen bond (see the following chemical formula), and as a result, the stability of the aminohydroxybenzophenone derivative or a salt thereof is improved by the conventional ultraviolet absorber (particularly UVA absorption). It is presumed that it has a higher stability than that of the agent and can be used for a long time.

[Method for producing aminohydroxybenzophenone derivative or salt thereof]
The aminohydroxybenzophenone derivative or salt thereof represented by (I) of the present invention can be produced by a known reaction using a readily available raw material (for example, 3-halogenated phenol). A scheme (scheme 1) of a synthesis example of the aminohydroxybenzophenone derivative or a salt thereof is shown as an example, but the aminohydroxybenzophenone derivative or salt thereof represented by (I) of the present invention is obtained by the following synthesis example. It is not limited to that.

  Compound (C) can be produced, for example, by reacting Compound (A) or a salt thereof with Compound (B) using a Lewis acid catalyst (Step 1). For the above reaction, it is preferable to use, for example, a Friedel-Crafts reaction.

  Said Y should just be a functional group which can be substituted and desorbed by the nucleophilic attack of the amine compound (F) in a later step. Examples of Y include fluorine, chlorine, bromine, iodine, or sulfonic acid ester groups such as a methanesulfonyl group, p-toluenesulfonyl group, nitrobenzenesulfonyl group, and trifluoromethanesulfonyl group. Among these, from the viewpoint of reaction yield and the like, preferred examples of Y include fluorine, chlorine, bromine, and iodine.

For the above R ⁶ and m of the compound (A), structures corresponding to the target products of the compound (G) and the compound (I) can be used.

  Examples of the compound (A) include 3-fluorophenol, 3-chlorophenol, 3-bromophenol, 3-iodophenol, 3-fluoro-5-methyl-phenol, 3-chloro-5-methyl-phenol, 3- Examples thereof include bromo-5-methyl-phenol and 3-iodo-5-methyl-phenol.

For R ⁷ and n in the compound (B), structures corresponding to the target products of the compound (G) and the compound (I) can be used.

  Examples of the compound (B) include phthalic anhydride, 3-methylphthalic anhydride, 4-methylphthalic anhydride, 4-tert-butylphthalic anhydride, 4-carboxyphthalic anhydride, and the like. . Moreover, it can replace with a compound (B) and the monoacyl derivative etc. which protected one carboxyl group of phthalic acid can also be used.

In the reaction (step 1), as the Lewis acid catalyst, a Lewis acid catalyst that can be used in a known Friedel-Crafts reaction or the like can be appropriately used. Examples of the Lewis acid catalyst include aluminum chloride (AlCl ₃ ), antimony chloride (SbCl ₅ ), iron chloride (FeCl ₃ ), titanium chloride (TiCl ₄ ), bismuth chloride (BiCl ₃ ), and zinc chloride (ZnCl ₂ ). Can give.

  In the above reaction (step 1), the molar ratio of compound (B) to compound (A) (mol of compound (B) / mol of compound (A)) is, for example, 1.0 to 3.0 (mol / mol). It is preferable to be performed at 1.0 to 2.0 (mol / mol).

  In the reaction (step 1), the molar ratio of the Lewis acid catalyst to the compound (A) (mol of the Lewis acid catalyst / mol of the compound (A)) is, for example, 1.0 to 3.0 (mol / mol). It is preferable to be performed at 1.0 to 2.0 (mol / mol).

  In the above reaction (step 1), each of the raw materials (and catalyst, etc.) may be appropriately performed in a solution, and when the raw material is a solvent, only the raw materials may be mixed and used as a reaction solution. As the solvent in the case of the above solution, a known solvent can be appropriately used. Examples of the solvent include benzene, toluene, xylene, nitrobenzene, chlorobenzene, dichloroethane, trichloroethane, tetrachloroethane, and the like. These solvents may be used alone or in combination of two or more.

  In the said reaction (step1), reaction temperature can be performed at 80-180 degreeC, for example, and it is preferable to be performed at 100-160 degreeC.

  In the above reaction (step 1), the reaction time can be, for example, 1 to 24 hours, and preferably 2 to 12 hours.

  In the reaction (step 1), a known purification method can be appropriately used for generating the reaction product. Examples of the purification method include silica gel column chromatography, high performance liquid chromatography, gas chromatography, gel permeation chromatography, recrystallization method, reprecipitation method, solvent extraction method, distillation, vacuum distillation and the like. These purification methods may be used alone or in combination of two or more.

  Compound (E) (compound (II) above) can be produced, for example, by reacting compound (C) or a salt thereof with compound (D) (Step 2).

R ¹⁴ may be any functional group that can be substituted / eliminated by a nucleophilic attack of the amine compound (F) in a later step. Examples of R ¹⁴ include —O—R ¹⁵ , fluorine, chlorine, bromine, or iodine.

Examples of R ¹⁵ include a linear or branched alkyl group having 1 to 4 carbon atoms. Examples of the linear or branched alkyl group having 1 to 4 carbon atoms in R ¹⁵ include a methyl group, an ethyl group, a 1-propyl group, a 1-methyl-1-ethyl group, a 1-butyl group, 1- Examples thereof include a methyl-1-propyl group, a 1,1-dimethyl-1-ethyl group, and a 2-methyl-1-propyl group. From the viewpoint of ease of handling during the synthesis reaction, the alkyl group preferably has an integer of 1 to 2 (that is, a methyl group or an ethyl group).

In the above reaction (step 2), when —C (═O) R ¹⁴ forms an ester structure, the compound (D) is an alcohol (or a hydroxyl group-containing structure) or the alcohol precursor, and is a known esterification. A reaction can be used. Examples of the esterification reaction include a method of heating using a known acid catalyst and a method of using a condensing agent such as N, N′-dicyclohexylcarbodiimide (DCC).

  As the acid catalyst, a known acid catalyst can be appropriately used. Examples of the acid catalyst include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, benzoic acid, salicylic acid, phthalic acid, p-toluenesulfonic acid, and the like. These acid catalysts may be used alone or in combination of two or more.

In the above reaction (step 2), when —C (═O) R ¹⁴ forms an acyl halide structure (for example, an acid chloride derivative), a halogenating reagent or the like is used instead of the compound (D), A known halogenation reaction can be appropriately used.

  Examples of the halogenating reagent include thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide and the like. These compounds may be used alone or in combination of two or more.

  In the reaction (step 2), the molar ratio of the compound (D) to the compound (C) (mol of the compound (C) / mol of the compound (D)) is, for example, 10 to 100 (mol / mol). It can be carried out at 20 to 80 (mol / mol).

  In the reaction (step 2), the amount of the acid catalyst added to the compound (C) can be appropriately added by using a known method. For example, it can be added to a 10 ml solution of compound (C) (0.5 to 5 g) with a 5 ml pipette in the range of 1 to 10 drops, preferably 3 to 5 drops. it can. In addition, when the acid catalyst can be used as a solvent, the compound (C) may be directly dissolved or suspended in the reaction using the catalyst as a solvent.

  In the above reaction (step 2), the above reaction may be carried out by appropriately using the respective raw materials (and catalyst, etc.) in a solution. When the raw material is a solvent, only the raw materials may be mixed and used as a reaction solution. In particular, it is preferable to use an alcohol compound that is liquid at normal temperature (25 ° C.) as the compound (D), and mix only raw materials to use as a reaction solution. As the solvent in the case of the above solution, a known solvent can be appropriately used. Examples of the solvent include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, and the like. These solvents may be used alone or in combination of two or more.

  In the said reaction (step2), reaction temperature can be performed at 80-140 degreeC, for example, and it is preferable to be performed at 100-120 degreeC. In particular, in an esterification reaction or the like, a method of distilling off water generated by condensation and shifting the equilibrium of the reaction (increasing the reaction conversion rate) may be used.

  In the above reaction (step 2), the reaction time can be, for example, 2 to 48 hr, and preferably 4 to 24 hr.

  In the reaction (step 2), a known purification method can be appropriately used for generating the reaction product. Examples of the purification method include silica gel column chromatography, high performance liquid chromatography, gas chromatography, gel permeation chromatography, recrystallization method, reprecipitation method, solvent extraction method, distillation, vacuum distillation and the like. These purification methods may be used alone or in combination of two or more.

  Compound (G) (compound (IV) above) can be produced, for example, by reacting compound (E) (compound (III) or salt thereof with compound (F) or salt thereof (Step 3). .

In the compound (F), R ¹ and R ² are each independently a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ⁸ —O) It represents a _p -R ^9. For R ¹ and R ² of the compound (F), an amine having a structure corresponding to the target product compound (G) or a salt thereof can be used. The compound (F) is a compound in which X is CONR ¹ R ² in the above compound (I). Thus, the compound in which X is CONR ¹ R ² is obtained particularly simply and in a high yield by the above reaction. be able to.

As the amidation reaction, a known amidation reaction can be used. As the amidation reaction, when —C (═O) R ¹⁴ forms an ester structure, for example, a method in which a molar equivalent or more of compound (F) is added and heat-treated can be used. In addition, when —C (═O) R ¹⁴ forms an acyl halide structure (for example, an acid chloride derivative), for example, a nucleophilic compound such as pyridine is used to remove the generated chlorine anion from the reaction system. Examples thereof include a method in which the compound (F) which is a low base or an amine is added to a molar equivalent or more and heated. In the amidation reaction, a known catalyst may be appropriately used.

  Examples of the compound (F) include N-hydroxymethyl-N-methylamine, N-1-hydroxyethyl-N-ethylamine, N-2-hydroxyethyl-N-ethylamine, N-1-hydroxypropyl-N-propyl. Ethylamine, N-2-hydroxypropyl-N-propylethylamine, N-3-hydroxypropyl-N-propylethylamine, N-1-hydroxybutyl-N-propylbutylamine, N-2-hydroxybutyl-N-propylbutylamine, N-3-hydroxybutyl-N-propylbutylamine, N-4-hydroxybutyl-N-propylbutylamine, N-1-hydroxyethyl-N-methylamine, N-2-hydroxyethyl-N-methylamine, N- 1-hydroxypropyl-N-propylmethylamino N-2-hydroxypropyl-N-propylmethylamine, N-3-hydroxypropyl-N-propylmethylamine, N-1-hydroxybutyl-N-propylmethylamine, N-2-hydroxybutyl-N-propyl Methylamine, N-3-hydroxybutyl-N-propylmethylamine, N-4-hydroxybutyl-N-propylmethylamine, N, N-dihydroxymethylamine, N, N-di (1-hydroxyethyl) amine, N, N-di (2-hydroxyethyl) amine, N, N-di (1-hydroxypropyl) amine, N, N-di (2-hydroxypropyl) amine, N, N-di (3-hydroxypropyl) Amine, N, N-di (1-hydroxybutyl) amine, N, N-di (2-hydroxybutyl) amine, N, N-di ( -Hydroxybutyl) amine, N, N-di (4-hydroxybutyl) amine, 2-hydroxy-1-pyrrolidine, 3-hydroxy-1-pyrrolidine, 2,3-dihydroxy-1-pyrrolidine, 2-hydroxy-3 -Methyl-1-pyrrolidine, 3-hydroxy-2-methyl-1-pyrrolidine, 2-hydroxy-3-ethyl-1-pyrrolidine, 3-hydroxy-2-ethyl-1-pyrrolidine, 2,4-dihydroxy-3 -Methyl-1-pyrrolidine, 2,3-dihydroxy-2-methyl-1-pyrrolidine, 2,4-hydroxy-3-ethyl-1-pyrrolidine, 2,3-hydroxy-2-ethyl-1-pyrrolidine, 2 -Hydroxy-1-piperidine, 3-hydroxy-1-piperidine, 4-hydroxy-1-pyrrolidine, 2,3-dihydroxy-1- Piperidine, 2-hydroxy-3-methyl-1-piperidine, 3-hydroxy-2-methyl-1-piperidine, 4-hydroxy-2-methyl-1-piperidine, 4-hydroxy-3-methyl-1-piperidine, 2,4-dihydroxy-3-methyl-1-piperidine, 2,5-dihydroxy-3-methyl-1-piperidine, 3,4-dihydroxy-2-methyl-1-piperidine, 3,5-dihydroxy-2- Methyl-1-piperidine, 3,4-hydroxy-2-methyl-1-piperidine, 2-hydroxymethyl-1-pyrrolidine, 3-hydroxymethyl-1-pyrrolidine, 2,3-di (hydroxymethyl) -1- Pyrrolidine, 2-hydroxymethyl-3-methyl-1-pyrrolidine, 3-hydroxymethyl-2-methyl-1-pyrrolidine, 2-H Loxyethyl-1-pyrrolidine, 3-hydroxyethyl-1-pyrrolidine, 2-hydroxyethyl-3-methyl-1-pyrrolidine, 3-hydroxyethyl-2-methyl-1-pyrrolidine, 2-hydroxymethyl-1-piperidine, 3-hydroxymethyl-1-piperidine, 4-hydroxymethyl-1-piperidine, 2,3-dihydroxymethyl-1-piperidine, 2,4-dihydroxymethyl-1-piperidine, 3,4-dihydroxymethyl-1-piperidine 2-hydroxymethyl-3-methyl-1-piperidine, 3-hydroxymethyl-2-methyl-1-piperidine, 4-hydroxymethyl-2-methyl-1-piperidine, 4-hydroxymethyl-3-methyl-1 -Piperidine, 2-hydroxyethyl-1-piperidine, 3-hydroxy Ethyl-1-piperidine, 4-hydroxyethyl-1-piperidine, 2-hydroxyethyl-3-methyl-1-piperidine, 3-hydroxyethyl-2-methyl-1-piperidine, 4-hydroxyethyl-2-methyl- Examples thereof include 1-piperidine, 4-hydroxyethyl-3-methyl-1-piperidine and the like.

As the catalyst, a known catalyst can be appropriately used. Examples of the catalyst include tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine, pyrrolidine and piperidine, and aromatic amines having low nucleophilicity such as pyridine and 4-dimethylaminopyridine. These catalysts may be used alone or in combination of two or more. In particular, when acid chloride is used as —C (═O) R ¹⁴ , the above-described low nucleophilic tertiary amine or aromatic amine is added as an acceptor of chloride ion in an equivalent amount or in excess. Alternatively, a method of shifting the equilibrium of the reaction (increasing the reaction conversion rate) may be used.

  In the reaction (step 3), the molar ratio of the compound (F) to the compound (E) (mol of the compound (F) / mol of the compound (E)) is, for example, 2-10 (mol / mol). It can be carried out at 4 to 8 (mol / mol).

  In the reaction (step 2), the molar ratio of the catalyst to the compound (E) (mol of the catalyst / mol of the compound (E)) can be performed at, for example, 0.01 to 1 (mol / mol), It is preferable to be carried out at 0.05 to 0.5 (mol / mol).

  In the above reaction (step 3), each of the raw materials (and catalyst, etc.) may be appropriately performed in a solution. When the raw material is a solvent, only the raw materials may be mixed and used as a reaction solution. In particular, it is preferable to use amines that are liquid at room temperature (25 ° C.) as the compound (F), and mix only raw materials to use as a reaction solution. As the solvent in the case of the above solution, a known solvent can be appropriately used. Examples of the solvent include N-hydroxymethyl-N-methylamine, N-1-hydroxyethyl-N-ethylamine, N-2-hydroxyethyl-N-ethylamine, N-1-hydroxypropyl-N-propylethylamine, N-2-hydroxypropyl-N-propylethylamine, N-3-hydroxypropyl-N-propylethylamine, N-1-hydroxybutyl-N-propylbutylamine, N-2-hydroxybutyl-N-propylbutylamine, N- 3-hydroxybutyl-N-propylbutylamine, N-4-hydroxybutyl-N-propylbutylamine, N-1-hydroxyethyl-N-methylamine, N-2-hydroxyethyl-N-methylamine, N-1- Hydroxypropyl-N-propylmethylamine, 2-hydroxypropyl-N-propylmethylamine, N-3-hydroxypropyl-N-propylmethylamine, N-1-hydroxybutyl-N-propylmethylamine, N-2-hydroxybutyl-N-propylmethylamine N-3-hydroxybutyl-N-propylmethylamine, N-4-hydroxybutyl-N-propylmethylamine, N, N-dihydroxymethylamine, N, N-di (1-hydroxyethyl) amine, N, N-di (2-hydroxyethyl) amine, N, N-di (1-hydroxypropyl) amine, N, N-di (2-hydroxypropyl) amine, N, N-di (3-hydroxypropyl) amine, N, N-di (1-hydroxybutyl) amine, N, N-di (2-hydroxybutyl) amine, N, N-di (3- Droxybutyl) amine, N, N-di (4-hydroxybutyl) amine, 2-hydroxy-1-pyrrolidine, 3-hydroxy-1-pyrrolidine, 2,3-dihydroxy-1-pyrrolidine, 2-hydroxy-3-methyl -1-pyrrolidine, 3-hydroxy-2-methyl-1-pyrrolidine, 2-hydroxy-3-ethyl-1-pyrrolidine, 3-hydroxy-2-ethyl-1-pyrrolidine, 2,4-dihydroxy-3-methyl -1-pyrrolidine, 2,3-dihydroxy-2-methyl-1-pyrrolidine, 2,4-hydroxy-3-ethyl-1-pyrrolidine, 2,3-hydroxy-2-ethyl-1-pyrrolidine, 2-hydroxy -1-piperidine, 3-hydroxy-1-piperidine, 4-hydroxy-1-pyrrolidine, 2,3-dihydroxy-1-pipe Lysine, 2-hydroxy-3-methyl-1-piperidine, 3-hydroxy-2-methyl-1-piperidine, 4-hydroxy-2-methyl-1-piperidine, 4-hydroxy-3-methyl-1-piperidine, 2,4-dihydroxy-3-methyl-1-piperidine, 2,5-dihydroxy-3-methyl-1-piperidine, 3,4-dihydroxy-2-methyl-1-piperidine, 3,5-dihydroxy-2- Methyl-1-piperidine, 3,4-hydroxy-2-methyl-1-piperidine, 2-hydroxymethyl-1-pyrrolidine, 3-hydroxymethyl-1-pyrrolidine, 2,3-di (hydroxymethyl) -1- Pyrrolidine, 2-hydroxymethyl-3-methyl-1-pyrrolidine, 3-hydroxymethyl-2-methyl-1-pyrrolidine, 2-hydro Cyethyl-1-pyrrolidine, 3-hydroxyethyl-1-pyrrolidine, 2-hydroxyethyl-3-methyl-1-pyrrolidine, 3-hydroxyethyl-2-methyl-1-pyrrolidine, 2-hydroxymethyl-1-piperidine, 3-hydroxymethyl-1-piperidine, 4-hydroxymethyl-1-piperidine, 2,3-dihydroxymethyl-1-piperidine, 2,4-dihydroxymethyl-1-piperidine, 3,4-dihydroxymethyl-1-piperidine 2-hydroxymethyl-3-methyl-1-piperidine, 3-hydroxymethyl-2-methyl-1-piperidine, 4-hydroxymethyl-2-methyl-1-piperidine, 4-hydroxymethyl-3-methyl-1 -Piperidine, 2-hydroxyethyl-1-piperidine, 3-hydroxyethyl 1-piperidine, 4-hydroxyethyl-1-piperidine, 2-hydroxyethyl-3-methyl-1-piperidine, 3-hydroxyethyl-2-methyl-1-piperidine, 4-hydroxyethyl-2-methyl- Examples thereof include 1-piperidine, 4-hydroxyethyl-3-methyl-1-piperidine and the like. These solvents may be used alone or in combination of two or more.

  In the above reaction (step 3), the reaction temperature can be, for example, 80 to 180 ° C, preferably 100 to 160 ° C. Moreover, you may use the method of distilling the reaction material produced by reaction, and shifting the equilibrium of reaction (raising reaction conversion rate).

  In the above reaction (step 3), the reaction time can be, for example, 2 to 48 hr, and preferably 4 to 24 hr.

  In the reaction (step 3), a known purification method can be appropriately used for generating the reaction product. Examples of the purification method include silica gel column chromatography, high performance liquid chromatography, gas chromatography, gel permeation chromatography, recrystallization method, reprecipitation method, solvent extraction method, distillation, vacuum distillation and the like. These purification methods may be used alone or in combination of two or more.

  Compound (I) (the above compound (VI)) can be produced, for example, by reacting compound (G) or a salt thereof with compound (H) (the above compound (V)) or a salt thereof (Step 4). it can.

In the compound (H), R ³ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ¹⁰ —O) _q —R ¹¹ . For R ³ of compound (F), an amine having a structure corresponding to compound (I) as the target product or a salt thereof can be used.

  As the esterification reaction, a known esterification reaction can be used. As the esterification reaction, for example, a method of heating by adding an acid catalyst, a method of adding a molar equivalent or more of the compound (H) to (G) first subjected to a hydrolysis reaction (acid catalyst, basic catalyst), and heating treatment The method in which esterification with compound (H) is carried out after hydrolysis of compound (G) or after conversion directly from compound (G) into a leaving group that is advantageous for esterification nucleophilic substitution reaction, hydrolysis Examples thereof include a method of reacting compound (G) with compound (H) using a condensing agent or the like.

Examples of R ³ —OH include 1,2-dihydroxyethane, 1,2-dihydroxypropylene, 1,3-dihydroxypropylene, 1,2-dihydroxybutyl group, 1,3-dihydroxybutyl group, 1,2 -Dihydroxy-2-methylpropane, 1,3-dihydroxy-2-methylpropane and the like can be mentioned. From the viewpoint that higher absorbance (absorbance of ultraviolet rays per mass) can be exhibited, the alkyl group preferably has an integer of 1 to 2 (that is, a methyl group or an ethyl group).

  As the acid catalyst in the hydrolysis reaction, a known acid catalyst can be appropriately used. Examples of the acid catalyst include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, benzoic acid, salicylic acid, phthalic acid, p-toluenesulfonic acid, and the like. These acid catalysts may be used alone or in combination of two or more.

  As the basic catalyst in the hydrolysis reaction, a known basic catalyst can be appropriately used. Examples of the basic catalyst include organic amines such as sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, triethylamine and pyridine. These basic catalysts may be used alone or in combination of two or more.

  In the above reaction (step 4), the molar ratio of compound (H) to compound (G) (mol of compound (H) / mol of compound (G)) is carried out, for example, at 10 to 100 (mol / mol). It can be carried out at 20 to 80 (mol / mol).

  In the reaction (step 4), the amount of the catalyst added to the compound (G) can be appropriately added by using a known method. For example, it can be added to a 10 ml solution of compound (G) (0.5 to 5 g) with a 5 ml pipette in the range of 1 to 10 drops, preferably 3 to 5 drops. it can. Further, when the catalyst can be used as a solvent, the compound (G) may be directly dissolved or suspended in the reaction using the catalyst as a solvent.

  In the above reaction (step 4), each of the raw materials (and catalyst, etc.) may be appropriately performed in a solution in the above reaction. When the raw material becomes a solvent, only the raw materials may be mixed and used as a reaction solution. In particular, in the case of a method in which only hydrolysis is performed first, a method in which concentrated sulfuric acid or concentrated hydrochloric acid is added to the liquid compound (G) and heat treatment can be used. As a solvent in the case of preparing the solution, a known solvent such as water can be appropriately used as necessary. These solvents may be used alone or in combination of two or more.

  In the said reaction (step4), reaction temperature can be performed at 80-180 degreeC, for example, and it is preferable to be performed at 100-160 degreeC. In particular, in an esterification reaction or the like, a method of distilling off water generated by condensation and shifting the equilibrium of the reaction (increasing the reaction conversion rate) may be used.

  In the above reaction (step 4), the reaction time can be, for example, 2 to 48 hr, and preferably 4 to 24 hr.

  In the reaction (step 4), a known purification method can be appropriately used for generating the reaction product. Examples of the purification method include silica gel column chromatography, high performance liquid chromatography, gas chromatography, gel permeation chromatography, recrystallization method, reprecipitation method, solvent extraction method, distillation, vacuum distillation and the like. These purification methods may be used alone or in combination of two or more.

Further, among the aminohydroxybenzophenone derivatives represented by (I) of the present invention or salts thereof, the compound (K) shows a scheme (scheme 2) of a synthesis example of a compound or a salt thereof in which X is CONR ³ R ⁴ .

  Compound (K) can be produced, for example, by reacting compound (G) or a salt thereof with compound (J) or a salt thereof (Step 5).

In the compound (J), R ⁴ and R ⁵ are each independently a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ¹² —O) r—R ¹³ (wherein, one of R ^{4 and} R ⁵ may be a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms). As for R ⁴ and R ⁵ of the compound (K), an amine having a structure corresponding to the target product compound (G) or a salt thereof can be used.

  As said amidation reaction, a well-known hydrolysis reaction and amidation reaction can be used, for example. Examples of the hydrolysis reaction include a method in which an acid catalyst or a basic catalyst is added and heated. In addition, as the amidation reaction, for example, a method of adding a molar equivalent amount or more of the compound (J) to the hydrolyzed (G) and heat-treating the compound (G) after hydrolysis or directly from the compound (G) A method of amidation with compound (J) after conversion to a leaving group that makes amidation nucleophilic substitution advantageous, using hydrolyzed compound (G) and compound (J) using a condensing agent or the like The reaction method etc. can be mention | raise | lifted. In the amidation reaction, a known catalyst may be appropriately used.

  Examples of the compound (J) include N-hydroxymethyl-N-methylamine, N-1-hydroxyethyl-N-ethylamine, N-2-hydroxyethyl-N-ethylamine, N-1-hydroxypropyl-N-propyl. Ethylamine, N-2-hydroxypropyl-N-propylethylamine, N-3-hydroxypropyl-N-propylethylamine, N-1-hydroxybutyl-N-propylbutylamine, N-2-hydroxybutyl-N-propylbutylamine, N-3-hydroxybutyl-N-propylbutylamine, N-4-hydroxybutyl-N-propylbutylamine, N-1-hydroxyethyl-N-methylamine, N-2-hydroxyethyl-N-methylamine, N- 1-hydroxypropyl-N-propylmethylamino N-2-hydroxypropyl-N-propylmethylamine, N-3-hydroxypropyl-N-propylmethylamine, N-1-hydroxybutyl-N-propylmethylamine, N-2-hydroxybutyl-N-propyl Methylamine, N-3-hydroxybutyl-N-propylmethylamine, N-4-hydroxybutyl-N-propylmethylamine, N, N-dihydroxymethylamine, N, N-di (1-hydroxyethyl) amine, N, N-di (2-hydroxyethyl) amine, N, N-di (1-hydroxypropyl) amine, N, N-di (2-hydroxypropyl) amine, N, N-di (3-hydroxypropyl) Amine, N, N-di (1-hydroxybutyl) amine, N, N-di (2-hydroxybutyl) amine, N, N-di ( -Hydroxybutyl) amine, N, N-di (4-hydroxybutyl) amine, 2-hydroxy-1-pyrrolidine, 3-hydroxy-1-pyrrolidine, 2,3-dihydroxy-1-pyrrolidine, 2-hydroxy-3 -Methyl-1-pyrrolidine, 3-hydroxy-2-methyl-1-pyrrolidine, 2-hydroxy-3-ethyl-1-pyrrolidine, 3-hydroxy-2-ethyl-1-pyrrolidine, 2,4-dihydroxy-3 -Methyl-1-pyrrolidine, 2,3-dihydroxy-2-methyl-1-pyrrolidine, 2,4-hydroxy-3-ethyl-1-pyrrolidine, 2,3-hydroxy-2-ethyl-1-pyrrolidine, 2 -Hydroxy-1-piperidine, 3-hydroxy-1-piperidine, 4-hydroxy-1-pyrrolidine, 2,3-dihydroxy-1- Piperidine, 2-hydroxy-3-methyl-1-piperidine, 3-hydroxy-2-methyl-1-piperidine, 4-hydroxy-2-methyl-1-piperidine, 4-hydroxy-3-methyl-1-piperidine, 2,4-dihydroxy-3-methyl-1-piperidine, 2,5-dihydroxy-3-methyl-1-piperidine, 3,4-dihydroxy-2-methyl-1-piperidine, 3,5-dihydroxy-2- Methyl-1-piperidine, 3,4-hydroxy-2-methyl-1-piperidine, 2-hydroxymethyl-1-pyrrolidine, 3-hydroxymethyl-1-pyrrolidine, 2,3-di (hydroxymethyl) -1- Pyrrolidine, 2-hydroxymethyl-3-methyl-1-pyrrolidine, 3-hydroxymethyl-2-methyl-1-pyrrolidine, 2-H Loxyethyl-1-pyrrolidine, 3-hydroxyethyl-1-pyrrolidine, 2-hydroxyethyl-3-methyl-1-pyrrolidine, 3-hydroxyethyl-2-methyl-1-pyrrolidine, 2-hydroxymethyl-1-piperidine, 3-hydroxymethyl-1-piperidine, 4-hydroxymethyl-1-piperidine, 2,3-dihydroxymethyl-1-piperidine, 2,4-dihydroxymethyl-1-piperidine, 3,4-dihydroxymethyl-1-piperidine 2-hydroxymethyl-3-methyl-1-piperidine, 3-hydroxymethyl-2-methyl-1-piperidine, 4-hydroxymethyl-2-methyl-1-piperidine, 4-hydroxymethyl-3-methyl-1 -Piperidine, 2-hydroxyethyl-1-piperidine, 3-hydroxy Ethyl-1-piperidine, 4-hydroxyethyl-1-piperidine, 2-hydroxyethyl-3-methyl-1-piperidine, 3-hydroxyethyl-2-methyl-1-piperidine, 4-hydroxyethyl-2-methyl- Examples thereof include 1-piperidine, 4-hydroxyethyl-3-methyl-1-piperidine and the like.

  As the acid catalyst in the hydrolysis reaction, a known acid catalyst can be appropriately used. Examples of the acid catalyst include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, benzoic acid, salicylic acid, phthalic acid, p-toluenesulfonic acid, and the like. These acid catalysts may be used alone or in combination of two or more.

  As the basic catalyst in the hydrolysis reaction, a known basic catalyst can be appropriately used. Examples of the basic catalyst include organic amines such as sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, triethylamine and pyridine. These basic catalysts may be used alone or in combination of two or more.

  As the amidation catalyst, a known catalyst can be appropriately used. Examples of the catalyst include tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine, pyrrolidine and piperidine, and aromatic amines having low nucleophilicity such as pyridine and 4-dimethylaminopyridine. These catalysts may be used alone or in combination of two or more. In particular, when compound (G) is once converted to acid chloride for amidation, the above-described low nucleophilic tertiary amine or aromatic amine is used as an acceptor of chloride ion in an equivalent amount or in excess. In addition to the above, a method of shifting the equilibrium of the reaction (increasing the reaction conversion rate) may be used.

  In the reaction (step 5), the molar ratio of the compound (J) to the compound (G) (mol of the compound (J) / mol of the compound (G)) is, for example, 10 to 100 (mol / mol). It can be carried out at 20 to 80 (mol / mol).

  In the reaction (step 5), the amount of the catalyst to be added to the compound (G) can be appropriately added by using a known method. For example, it can be added to a 10 ml solution of compound (G) (0.5 to 5 g) with a 5 ml pipette in the range of 1 to 10 drops, preferably 3 to 5 drops. it can. Further, when the catalyst can be used as a solvent, the compound (G) may be directly dissolved or suspended in the reaction using the catalyst as a solvent.

  In the reaction (step 5), the molar ratio of the amidation catalyst to the compound (G) (mol of the catalyst / mol of the compound (G)) is, for example, 0.01 to 1 (mol / mol). Preferably, it is carried out at 0.05 to 0.5 (mol / mol).

  In the above reaction (step 5), each of the raw materials (and catalyst, etc.) may be appropriately performed in a solution in the above reaction. When the raw material becomes a solvent, only the raw materials may be mixed and used as a reaction solution. In particular, it is preferable to use amines that are liquid at room temperature (25 ° C.) as the compound (J), and mix only raw materials to use as a reaction solution. As the solvent in the case of the above solution, a known solvent can be appropriately used. Examples of the solvent include N-hydroxymethyl-N-methylamine, N-1-hydroxyethyl-N-ethylamine, N-2-hydroxyethyl-N-ethylamine, N-1-hydroxypropyl-N-propylethylamine, N-2-hydroxypropyl-N-propylethylamine, N-3-hydroxypropyl-N-propylethylamine, N-1-hydroxybutyl-N-propylbutylamine, N-2-hydroxybutyl-N-propylbutylamine, N- 3-hydroxybutyl-N-propylbutylamine, N-4-hydroxybutyl-N-propylbutylamine, N-1-hydroxyethyl-N-methylamine, N-2-hydroxyethyl-N-methylamine, N-1- Hydroxypropyl-N-propylmethylamine, 2-hydroxypropyl-N-propylmethylamine, N-3-hydroxypropyl-N-propylmethylamine, N-1-hydroxybutyl-N-propylmethylamine, N-2-hydroxybutyl-N-propylmethylamine N-3-hydroxybutyl-N-propylmethylamine, N-4-hydroxybutyl-N-propylmethylamine, N, N-dihydroxymethylamine, N, N-di (1-hydroxyethyl) amine, N, N-di (2-hydroxyethyl) amine, N, N-di (1-hydroxypropyl) amine, N, N-di (2-hydroxypropyl) amine, N, N-di (3-hydroxypropyl) amine, N, N-di (1-hydroxybutyl) amine, N, N-di (2-hydroxybutyl) amine, N, N-di (3- Droxybutyl) amine, N, N-di (4-hydroxybutyl) amine, 2-hydroxy-1-pyrrolidine, 3-hydroxy-1-pyrrolidine, 2,3-dihydroxy-1-pyrrolidine, 2-hydroxy-3-methyl -1-pyrrolidine, 3-hydroxy-2-methyl-1-pyrrolidine, 2-hydroxy-3-ethyl-1-pyrrolidine, 3-hydroxy-2-ethyl-1-pyrrolidine, 2,4-dihydroxy-3-methyl -1-pyrrolidine, 2,3-dihydroxy-2-methyl-1-pyrrolidine, 2,4-hydroxy-3-ethyl-1-pyrrolidine, 2,3-hydroxy-2-ethyl-1-pyrrolidine, 2-hydroxy -1-piperidine, 3-hydroxy-1-piperidine, 4-hydroxy-1-pyrrolidine, 2,3-dihydroxy-1-pipe Lysine, 2-hydroxy-3-methyl-1-piperidine, 3-hydroxy-2-methyl-1-piperidine, 4-hydroxy-2-methyl-1-piperidine, 4-hydroxy-3-methyl-1-piperidine, 2,4-dihydroxy-3-methyl-1-piperidine, 2,5-dihydroxy-3-methyl-1-piperidine, 3,4-dihydroxy-2-methyl-1-piperidine, 3,5-dihydroxy-2- Methyl-1-piperidine, 3,4-hydroxy-2-methyl-1-piperidine, 2-hydroxymethyl-1-pyrrolidine, 3-hydroxymethyl-1-pyrrolidine, 2,3-di (hydroxymethyl) -1- Pyrrolidine, 2-hydroxymethyl-3-methyl-1-pyrrolidine, 3-hydroxymethyl-2-methyl-1-pyrrolidine, 2-hydro Cyethyl-1-pyrrolidine, 3-hydroxyethyl-1-pyrrolidine, 2-hydroxyethyl-3-methyl-1-pyrrolidine, 3-hydroxyethyl-2-methyl-1-pyrrolidine, 2-hydroxymethyl-1-piperidine, 3-hydroxymethyl-1-piperidine, 4-hydroxymethyl-1-piperidine, 2,3-dihydroxymethyl-1-piperidine, 2,4-dihydroxymethyl-1-piperidine, 3,4-dihydroxymethyl-1-piperidine 2-hydroxymethyl-3-methyl-1-piperidine, 3-hydroxymethyl-2-methyl-1-piperidine, 4-hydroxymethyl-2-methyl-1-piperidine, 4-hydroxymethyl-3-methyl-1 -Piperidine, 2-hydroxyethyl-1-piperidine, 3-hydroxyethyl 1-piperidine, 4-hydroxyethyl-1-piperidine, 2-hydroxyethyl-3-methyl-1-piperidine, 3-hydroxyethyl-2-methyl-1-piperidine, 4-hydroxyethyl-2-methyl- Examples thereof include 1-piperidine, 4-hydroxyethyl-3-methyl-1-piperidine and the like. These solvents may be used alone or in combination of two or more.

  In the said reaction (step5), reaction temperature can be performed at 80-180 degreeC, for example, and it is preferable to be performed at 100-160 degreeC. Moreover, you may use the method of distilling the reaction material produced by reaction, and shifting the equilibrium of reaction (raising reaction conversion rate).

  In the above reaction (step 5), the reaction time can be, for example, 2 to 48 hr, and preferably 4 to 24 hr.

  In the above reaction (step 5), a known purification method can be appropriately used for generating the reaction product. Examples of the purification method include silica gel column chromatography, high performance liquid chromatography, gas chromatography, gel permeation chromatography, recrystallization method, reprecipitation method, solvent extraction method, distillation, vacuum distillation and the like. These purification methods may be used alone or in combination of two or more.

[Use of aminohydroxybenzophenone derivative or salt thereof]
(UV absorber)
The ultraviolet absorber of the present invention is characterized by containing the aminohydroxybenzophenone derivative or a salt thereof as an essential component. Therefore, the ultraviolet absorbent according to the present invention has hydrophilicity, is neutral, safer to the skin (and to the environment and the living body), and has an excellent ultraviolet A wave (UVA) absorption action. It becomes. In particular, it can be suitably used for an aqueous composition (such as an aqueous solution or an emulsion). Moreover, the said ultraviolet absorber may contain the arbitrary component as needed, respectively. The aminohydroxybenzophenone derivative or a salt thereof may be used alone or in combination of two or more.

  In the ultraviolet absorber, the content of the aminohydroxybenzophenone derivative (and its salt) relative to the ultraviolet absorber (total amount) can be, for example, 0.001 to 100 (% by weight), 0.1 More preferably, it is 10-10 weight%, More preferably, it is 0.1-1 weight%.

  As said arbitrary component, the well-known organic type ultraviolet absorber different from the said aminohydroxybenzophenone derivative or its salt, an inorganic powder type | system | group ultraviolet shielding agent, etc. can be mention | raise | lifted, for example. Moreover, you may use as an ultraviolet-absorbing composition, adding another arbitrary component suitably or adding in another arbitrary component.

(Skin external preparation)
The skin external preparation of the present invention is characterized by containing the aminohydroxybenzophenone derivative or a salt thereof as an essential component. For this reason, it is hydrophilic, neutral, safe to the skin, and has an excellent ultraviolet A wave (UVA) absorption action. In particular, UV exposure in human and animal hair and skin application sites. It is possible to reduce the damage caused by. Moreover, it can be used suitably for an aqueous skin external composition (aqueous solution type or emulsion type external composition for skin), and when washing the application site of the skin external preparation, the aminohydroxybenzophenone derivative or its salt is applied from the application site. High detergency that can be easily removed by washing without using a special cleaning agent can be exhibited. The above-mentioned external preparation for skin can be used as, for example, cosmetics, sunscreen compositions and the like. Moreover, the said skin external preparation may contain arbitrary components as needed, respectively. The aminohydroxybenzophenone derivative or a salt thereof may be used alone or in combination of two or more.

  In the external preparation for skin, the content of the aminohydroxybenzophenone derivative (and its salt) relative to the external preparation for skin (total amount) can be, for example, 0.1 to 100 (% by weight), 0.5 More preferably, it is -20 (weight%), More preferably, it is 1-10 (weight%).

  The aqueous skin external composition refers to a composition for external skin containing water, such as lotion, in an amount of 30 to 99% by weight per 100% by weight of the composition.

  Further, the aminohydroxybenzophenone derivative or a salt thereof does not have an acidic group such as a sulfonic acid group or a basic group as a basic structure, and does not significantly affect the pH of the external composition for skin. Therefore, the external preparation for skin of the present invention is safe to the skin and can contain known components without particular limitation.

  The above-mentioned external preparation for skin can be used as a sunscreen composition or the like that meets the current needs that are used in daily life and require good cleanability.

  Examples of the external preparation for skin of the present invention include, for example, the above-mentioned organic ultraviolet absorbers and inorganic powder ultraviolet shielding agents, liquid fats and oils, solid fats and oils, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters and silicones. , Anionic surfactant, cationic surfactant, amphoteric surfactant, nonionic surfactant, moisturizer, water-soluble polymer compound, thickener, coating agent, sequestering agent, lower alcohol, polyhydric alcohol Sugars, amino acids, organic amines, pH adjusters, skin nutrients, vitamins, antioxidants, fragrances, powders, coloring materials, water, and the like can be blended. These optional components may be used alone or in combination of two or more.

(Other uses)
The aminohydroxybenzophenone derivative or salt thereof of the present invention is a product other than a skin external preparation, for example, paint, dye, pigment, various resins, synthetic rubber, latex, packaging materials (films, synthetic resin containers, etc.), contact lenses or It is also possible to protect these paints and the like from ultraviolet rays as various compositions or products by blending with fibers and the like.

  Examples and the like specifically showing the configuration and effects of the present invention will be described below. In addition, the evaluation item in an Example etc. measured as follows.

<Measurement of UV spectrum>
The UV spectrum was measured using a spectrophotometer (manufactured by Shimadzu Corporation, UV-4250). More specifically, each UV spectrum was measured using ethanol as a solvent and a quartz cell having a sample solution concentration of 5 ppm and an optical path length of 1 cm. The absorbance was calculated according to Lambert-Beer's law, where Io was the transmitted light intensity of the empty cell and I was the transmitted light intensity of the sample cell, with absorbance = −log ₁₀ (I / I ₀ ). Further, the wavelength at which the absorbance in the obtained UV spectrum becomes maximum was defined as λmax (nm).

<Measurement of ¹ H-NMR spectrum>
¹ H-NMR spectrum was measured using a nuclear magnetic resonance apparatus (JNM-ECP500, manufactured by JEOL Ltd.). More specifically, each ¹ H-NMR spectrum was measured using DMSO-d ₆ as a solvent and tetramethylsilane as an internal standard.

<Evaluation of hydrophilicity>
The sample compound was dissolved in the following test solvent, the properties were confirmed, and the solubility (g / 100 g test solvent) with respect to 100 g of the test solvent at 25 ° C. was measured.

(Test solvent)
A mixed solvent containing dipropylene glycol, ethanol, and purified water in amounts of 10 mass%, 10 mass%, and 80 mass%, respectively, was used as a test solvent. However, the total amount of dipropylene glycol, ethanol, and purified water was 100% by mass.

(Evaluation method)
When the measured solubility is 1.0 (g / 100 g test solvent) or higher, the sample compound is evaluated as having hydrophilicity, while the solubility is 1.0 (g / 100 g test solvent). ), The sample compound was evaluated as not having hydrophilicity.

１００ｍｌナス型フラスコ中に、３−フルオロフェノール３．３６ｇ（３０ｍｍｏｌ）、フタル酸無水物４．８９ｇ（３３ｍｍｏｌ）、塩化アルミニウム８．００ｇ（６０ｍｍｏｌ）を加えて、１４０℃で３時間加熱した。反応混合液が室温まで冷えた後、水および２Ｎ塩酸を適量加え、クロロホルム１００ｍｌで３回抽出した。得られた有機層を合わせ、５Ｎ水酸化ナトリウム５０ｍｌで３回抽出した。得られた水層を合わせ、濃塩酸を加えてｐＨ１以下に調整した後、クロロホルム１００ｍｌで３回抽出した。得られた有機層を合わせ、水５０ｍｌで２回、飽和食塩水５０ｍｌで１回洗浄し、硫酸ナトリウムを用いて乾燥した。その後、硫酸ナトリウムをろ過して除去し、溶剤を減圧下で留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：酢酸エチル／ヘキサン＝１／４（Ｖ／Ｖ））を用いて精製し、２−（４−フルオロ−２−ヒドロキシベンゾイル）安息香酸（化合物（ａ））７４０ｍｇ（収率９．５％）を得た。 [Example 1]
<Synthesis of 2- [4-N-methyl-N- (2-hydroxyethyl) amino-2-hydroxybenzoyl] benzoic acid N-methyl-N- (2-hydroxyethyl) amide (compound (1))>

In a 100 ml eggplant type flask, 3.36 g (30 mmol) of 3-fluorophenol, 4.89 g (33 mmol) of phthalic anhydride and 8.00 g (60 mmol) of aluminum chloride were added and heated at 140 ° C. for 3 hours. After the reaction mixture was cooled to room temperature, appropriate amounts of water and 2N hydrochloric acid were added, and the mixture was extracted 3 times with 100 ml of chloroform. The obtained organic layers were combined and extracted three times with 50 ml of 5N sodium hydroxide. The obtained aqueous layers were combined, concentrated hydrochloric acid was added to adjust the pH to 1 or less, and the mixture was extracted 3 times with 100 ml of chloroform. The obtained organic layers were combined, washed twice with 50 ml of water and once with 50 ml of saturated saline, and dried using sodium sulfate. Thereafter, sodium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/4 (V / V)) to give 2- (4-fluoro-2-hydroxybenzoyl) benzoic acid (compound ( a)) 740 mg (yield 9.5%) were obtained.

  740 mg of the obtained compound (a) was added to a 30 ml eggplant-shaped flask, 3 ml of methanol and 3 drops of concentrated sulfuric acid were added with a pipette, and the mixture was heated with stirring under reflux for 14 hours. After the reaction mixture cooled to room temperature, an appropriate amount of water was added, and the mixture was extracted 3 times with 30 ml of ethyl acetate. The obtained organic layers were combined, washed once with 30 ml of 10% aqueous sodium hydrogen carbonate solution and once with 30 ml of saturated brine, and dried over sodium sulfate. Thereafter, sodium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/4 (V / V)) to give 2- (4-fluoro-2-hydroxybenzoyl) benzoic acid methyl ester ( 440 mg (yield 56%) of compound (b) was obtained.

  In a 30 ml eggplant-shaped flask, 384 mg (1.4 mmol) of the obtained compound (b) and 631 mg (8.4 mmol) of N-methylethanolamine were added and heated at 120 ° C. with stirring for 4 hours. The solvent was distilled off under reduced pressure to obtain a tan oily substance. The obtained substance was purified using silica gel column chromatography (developing solvent: chloroform / methanol = 50/1 → 20/1 (V / V)) to give 2- [4-N-methyl-N- (2- Hydroxyethyl) amino-2-hydroxybenzoyl] benzoic acid N-methyl-N- (2-hydroxyethyl) amide (compound (1)) (390 mg, yield 75%) was obtained. The compound (1) was hydrophilic (> 25 (g / 100 g test solvent)).

(Spectral data of compound (1))
UV spectrum: λmax; 362 nm, absorbance; 0.50 (ethanol)
¹ H-NMR spectrum: δ [ppm, DMSO-d ₆ ] = 2.87 (s, 3H), 3.04 (s, 3H), 3.37-3.39 (m, 2H), 3.43 -3.57 (m, 6H), 4.80 (t, 2H), 6.13 (d, 1H), 6.31 (dd, 1H), 7.09 (d, 1H), 7.43- 7.58 (m, 4H), 12.62 (s, 1H).

３０ｍｌナス型フラスコ中に、得られた化合物（１）１２７ｍｇ（０．３４ｍｍｏｌ）を加え、さらに濃塩酸２ｍｌを加え、１００℃で３時間撹拌しながら加熱した。薄層クロマトグラフィーを用いて化合物（１）が消失したことを確認した後、得られた黄褐色の液にジエチレングリコール２ｍｌを加えて、１３０℃で３時間撹拌しながら加熱した。溶剤を減圧下で留去し、黄褐色油状物質を得た。得られた物質をシリカゲルカラムクロマトグラフィー（展開溶媒：クロロホルム／メタノール＝２０／１（Ｖ／Ｖ））を用いて精製し、２−［４−Ｎ−メチル−Ｎ−（２−ヒドロキシエチル）アミノ−２−ヒドロキシベンゾイル］安息香酸 ２−（２−ヒドロキシエトキシ）エチルエステル（化合物（２））９３ｍｇ（収率６８％）を得た。また、上記化合物（２）は親水性を有するものであった（＞２５（ｇ／１００ｇ試験溶媒））。 [Example 2]
<Synthesis of 2- [4-N-methyl-N- (2-hydroxyethyl) amino-2-hydroxybenzoyl] benzoic acid 2- (2-hydroxyethoxy) ethyl ester (compound (2))>

In a 30 ml eggplant-shaped flask, 127 mg (0.34 mmol) of the obtained compound (1) was added, 2 ml of concentrated hydrochloric acid was further added, and the mixture was heated at 100 ° C. with stirring for 3 hours. After confirming the disappearance of compound (1) using thin layer chromatography, 2 ml of diethylene glycol was added to the resulting tan liquid, and the mixture was heated at 130 ° C. with stirring for 3 hours. The solvent was distilled off under reduced pressure to obtain a tan oily substance. The obtained substance was purified using silica gel column chromatography (developing solvent: chloroform / methanol = 20/1 (V / V)) to give 2- [4-N-methyl-N- (2-hydroxyethyl) amino. 2-hydroxybenzoyl] benzoic acid 2- (2-hydroxyethoxy) ethyl ester (compound (2)) 93 mg (yield 68%) was obtained. The compound (2) was hydrophilic (> 25 (g / 100 g test solvent)).

(Spectral data of compound (2))
UV spectrum: λmax; 353 nm, absorbance; 0.37 (ethanol)
¹ H-NMR spectrum: δ [ppm, DMSO-d ₆ ] = 3.02 (s, 3H), 3.34-3.37 (m, 2H), 3.42-3.45 (m, 2H) 3.46-3.50 (m, 2H), 3.53-3.56 (m, 4H), 4.20 (t, 2H), 4.60 (t, 1H), 4.79 (t 1H), 6.15 (d, 1H), 6.24 (dd, 1H), 6.81 (d, 1H), 7.44 (d, 1H), 7.66 (t, 1H), 7 .74 (t, 1H), 7.99 (d, 1H), 12.53 (s, 1H).

３０ｍｌナス型フラスコ中に、得られた化合物（１）４０９ｍｇ（１．１０ｍｍｏｌ）を加え、さらに濃塩酸３ｍｌを加え、１００℃で１時間撹拌しながら加熱した。薄層クロマトグラフィーを用いて化合物（１）が消失したことを確認した後、得られた黄褐色の液にテトラエチレングリコール３ｍｌを加えて、１３０℃で９時間撹拌しながら加熱した。溶剤を減圧下で留去し、黄褐色油状物質を得た。得られた物質をシリカゲルカラムクロマトグラフィー（展開溶媒：クロロホルム／メタノール＝２０／１（Ｖ／Ｖ））を用いて精製し、２−［４−Ｎ−メチル−Ｎ−（２−ヒドロキシエチル）アミノ−２−ヒドロキシベンゾイル］安息香酸 ２−（２−（２−（２−ヒドロキシエトキシ）エトキシ）エトキシ）エチルエステル（化合物（３））２０６ｍｇ（収率３８％）を得た。また、上記化合物（３）は親水性を有するものであった（＞２５（ｇ／１００ｇ試験溶媒））。 Example 3
<2- [4-N-methyl-N- (2-hydroxyethyl) amino-2-hydroxybenzoyl] benzoic acid 2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethyl ester (compound ( 3)) Synthesis>

In a 30 ml eggplant-shaped flask, 409 mg (1.10 mmol) of the obtained compound (1) was added, 3 ml of concentrated hydrochloric acid was further added, and the mixture was heated with stirring at 100 ° C. for 1 hour. After confirming the disappearance of compound (1) using thin layer chromatography, 3 ml of tetraethylene glycol was added to the resulting yellow-brown liquid and heated at 130 ° C. with stirring for 9 hours. The solvent was distilled off under reduced pressure to obtain a tan oily substance. The obtained substance was purified using silica gel column chromatography (developing solvent: chloroform / methanol = 20/1 (V / V)) to give 2- [4-N-methyl-N- (2-hydroxyethyl) amino. 2-hydroxybenzoyl] benzoic acid 2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethyl ester (compound (3)) 206 mg (yield 38%) was obtained. The compound (3) was hydrophilic (> 25 (g / 100 g test solvent)).

(Spectral data of compound (3))
UV spectrum: λmax; 352 nm, absorbance; 0.32 (ethanol)
¹ H-NMR spectrum: δ [ppm, DMSO-d ₆ ] = 3.02 (s, 3H), 3.36-3.40 (t, 2H), 3.44-3.45 (m, 4H) 3.46-3.51 (m, 8H), 3.52-3.56 (m, 4H), 4.19 (t, 2H), 4.59 (t, 1H), 4.78 (t 1H), 6.15 (d, 1H), 6.24 (dd, 1H), 6.82 (d, 1H), 7.44 (d, 1H), 7.66 (t, 1H), 7 .74 (t, 1H), 7.99 (d, 1H), 12.53 (s, 1H).

３０ｍｌナス型フラスコ中に、得られた化合物（ｂ）４１５ｍｇ（１．５ｍｍｏｌ）、およびジエタノールアミン９４６ｍｇ（９．０ｍｍｏｌ）を加え、１２０℃で１．５時間撹拌しながら加熱した。溶剤を減圧下で留去し、黄褐色油状物質２．１５ｇ得た。得られた物質をシリカゲルカラムクロマトグラフィー（展開溶媒：クロロホルム／メタノール＝２０／１→５／１（Ｖ／Ｖ））を用いて精製し、２−［４−Ｎ，Ｎ−ビス（２−ヒドロキシエチル）アミノ−２−ヒドロキシベンゾイル］安息香酸 Ｎ，Ｎ−ビス（２−ヒドロキシエチル）アミド（化合物（４））３８０ｍｇ（収率５９％）を得た。また、上記化合物（４）は親水性を有するものであった（＞２５（ｇ／１００ｇ試験溶媒））。 Example 4
<Synthesis of 2- [4-N, N-bis (2-hydroxyethyl) amino-2-hydroxybenzoyl] benzoic acid N, N-bis (2-hydroxyethyl) amide (compound (4))>

In a 30 ml eggplant type flask, 415 mg (1.5 mmol) of the obtained compound (b) and 946 mg (9.0 mmol) of diethanolamine were added and heated at 120 ° C. with stirring for 1.5 hours. The solvent was distilled off under reduced pressure to obtain 2.15 g of a tan oily substance. The obtained substance was purified using silica gel column chromatography (developing solvent: chloroform / methanol = 20/1 → 5/1 (V / V)) to give 2- [4-N, N-bis (2-hydroxy). Ethyl) amino-2-hydroxybenzoyl] benzoic acid N, N-bis (2-hydroxyethyl) amide (compound (4)) (380 mg, yield 59%) was obtained. The compound (4) was hydrophilic (> 25 (g / 100 g test solvent)).

(Spectral data of compound (4))
UV spectrum: λmax; 362 nm, absorbance; 0.45 (ethanol)
1H-NMR spectrum: δ [ppm, DMSO-d ₆ ] = 3.26 (t, 2H), 3.41-3.45 (m, 4H), 3.49-3.57 (m, 10H), 4.69 (t, 1H), 4.78 (t, 1H), 4.85 (t, 2H), 6.17 (d, 1H), 6.30 (dd, 1H), 7.05 (d 1H), 7.44-7.59 (m, 4H), 12.62 (s, 1H).

３０ｍｌナス型フラスコ中に、得られた化合物（４）３６０ｍｇ（０．０８３ｍｍｏｌ）を加え、さらに濃塩酸７ｍｌを加え、１２０℃で２時間撹拌しながら加熱した。薄層クロマトグラフィーを用いて化合物（４）が消失したことを確認した後、得られた黄褐色の液にジエチレングリコール３．５ｍｌを加えて、１２０℃で３時間撹拌しながら加熱した。溶剤を減圧下で留去し、黄褐色油状物質６４０ｍｇ得た。得られた物質をシリカゲルカラムクロマトグラフィー（展開溶媒：クロロホルム／メタノール＝２０／１（Ｖ／Ｖ））を用いて精製し、２−［４−Ｎ，Ｎ−ビス（２−ヒドロキシエチル）アミノ−２−ヒドロキシベンゾイル］安息香酸 ２−（２−ヒドロキシエトキシ）エチルエステル（化合物（５））１４９ｍｇ（収率４１％）を得た。また、上記化合物（５）は親水性を有するものであった（＞２５（ｇ／１００ｇ試験溶媒））。 Example 5
<Synthesis of 2- [4-N, N-bis (2-hydroxyethyl) amino-2-hydroxybenzoyl] benzoic acid 2- (2-hydroxyethoxy) ethyl ester (compound (5))>

In a 30 ml eggplant-shaped flask, 360 mg (0.083 mmol) of the obtained compound (4) was added, 7 ml of concentrated hydrochloric acid was further added, and the mixture was heated at 120 ° C. with stirring for 2 hours. After confirming the disappearance of compound (4) using thin layer chromatography, 3.5 ml of diethylene glycol was added to the resulting tan solution, and the mixture was heated at 120 ° C. with stirring for 3 hours. The solvent was distilled off under reduced pressure to obtain 640 mg of a tan oily substance. The obtained substance was purified using silica gel column chromatography (developing solvent: chloroform / methanol = 20/1 (V / V)) to give 2- [4-N, N-bis (2-hydroxyethyl) amino- 2-hydroxybenzoyl] benzoic acid 2- (2-hydroxyethoxy) ethyl ester (compound (5)) (149 mg, yield 41%) was obtained. The compound (5) was hydrophilic (> 25 (g / 100 g test solvent)).

(Spectral data of compound (5))
UV spectrum: λmax; 353 nm, absorbance; 0.37 (ethanol)
1H-NMR spectrum: δ [ppm, DMSO-d ₆ ] = 3.35-3.36 (m, 2H), 3.42-3.45 (m, 2H), 3.48-3.51 (m 4H), 3.54-3.56 (m, 6H), 4.21 (t, 2H), 4.59 (t, 1H), 4.84 (t, 2H), 6.18 (d, 1H), 6.24 (dd, 1H), 6.80 (d, 1H), 7.44 (d, 1H), 7.66 (t, 1H), 7.74 (t, 1H), 7. 99 (d, 1H), 12.51 (s, 1H).

３０ｍｌナス型フラスコ中に、得られた化合物（４）５５７ｍｇを加え、さらに濃塩酸３ｍｌを加え、１００℃で１時間撹拌しながら加熱した。薄層クロマトグラフィーを用いて化合物（４）が消失したことを確認した後、得られた黄褐色の液にテトラエチレングリコール３ｍｌを加えて、１３０℃で８時間撹拌しながら加熱した。溶剤を減圧下で留去し、黄褐色油状物質を得た。得られた物質をシリカゲルカラムクロマトグラフィー（展開溶媒：クロロホルム／メタノール＝２０／１（Ｖ／Ｖ））を用いて精製し、２−［４−Ｎ，Ｎ−ビス（２−ヒドロキシエチル）アミノ−２−ヒドロキシベンゾイル］安息香酸 ２−（２−（２−（２−ヒドロキシエトキシ）エトキシ）エトキシ）エチルエステル（化合物（６））２４８ｍｇ（収率３７％）を得た。また、上記化合物（６）は親水性を有するものであった（＞２５（ｇ／１００ｇ試験溶媒））。 Example 6
<2- [4-N, N-bis (2-hydroxyethyl) amino-2-hydroxybenzoyl] benzoic acid 2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethoxy) ethyl ester (compound Synthesis of (6))>

In a 30 ml eggplant-shaped flask, 557 mg of the obtained compound (4) was added, 3 ml of concentrated hydrochloric acid was further added, and the mixture was heated at 100 ° C. with stirring for 1 hour. After confirming the disappearance of compound (4) using thin layer chromatography, 3 ml of tetraethylene glycol was added to the resulting tan solution and heated at 130 ° C. with stirring for 8 hours. The solvent was distilled off under reduced pressure to obtain a tan oily substance. The obtained substance was purified using silica gel column chromatography (developing solvent: chloroform / methanol = 20/1 (V / V)) to give 2- [4-N, N-bis (2-hydroxyethyl) amino- 2-hydroxybenzoyl] benzoic acid 2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethyl ester (compound (6)) (248 mg, yield 37%) was obtained. The compound (6) was hydrophilic (> 25 (g / 100 g test solvent)).

(Spectral data of compound (6))
UV spectrum: λmax; 353 nm, absorbance; 0.31 (ethanol)
1H-NMR spectrum: δ [ppm, DMSO-d ₆ ] = 3.37-3.40 (m, 2H), 3.42-3.44 (m, 4H), 3.46-3.51 (m 10H), 3.53-3.56 (m, 6H), 4.20 (t, 2H), 4.60 (t, 1H), 4.84 (t, 2H), 6.18 (d, 1H), 6.24 (dd, 1H), 6.81 (d, 1H), 7.44 (d, 1H), 7.66 (t, 1H), 7.74 (t, 1H), 7. 99 (d, 1H), 12.52 (s, 1H).

[Examples 7 to 99]
In Example 1, except that the following amine compounds 1 to 93 were used instead of N-methylethanolamine, the same aminohydroxybenzophenone amide as in Example 1 was added (if necessary, a solvent or the like was added as appropriate). Derivatives (compounds (7) to (99)) can be obtained (see Tables 1 to 4).

[Examples 100 to 367]
In Example 2, the following aminohydroxybenzophenone amide derivative was used instead of compound (1), and the following alcohol compound was used instead of diethylene glycol, respectively. The following aminohydroxybenzophenone ester derivatives (compounds (100) to (387)) can be obtained (see Tables 5 to 12).

Claims (9)

An aminohydroxybenzophenone derivative represented by the general formula (I) or a salt thereof.

(In the formula, indefinite items have the following meanings independently of each other.
R ¹ and R ² each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ⁸ —O) _p —R ⁹ . (However, ^one of R ¹ or R ² may be a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), and NR ¹ R ² represents a 5- or 6-membered heterocycle. May be formed, the heterocycle is substituted with at least one hydroxyl group, and the heterocycle may be further substituted.
R ⁸ represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ⁹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, p Is an integer of 1 to 4, and when p is 2 or more, a plurality of R ⁸ may be the same or different.
X represents COOR ³ or CONR ⁴ R ⁵ , wherein R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ¹⁰ —O) _q represents -R ^{11, R 4} and ^{R 5} are each independently at least one linear or branched alkyl group having 1 to 4 carbon atoms which is substituted with a hydroxyl group ^{or,, - (R} 12 -O) _r— R ¹³ (wherein one of R ^{4 and} R ⁵ may be a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), and NR ⁴ R ⁵ is 5 or It may form a 6-membered heterocycle, and the heterocycle is substituted with at least one hydroxyl group, and the heterocycle may be further substituted.
R ¹⁰ represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ¹¹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, q Is an integer of 1 to 4, and when q is 2 or more, a plurality of R ¹⁰ may be the same or different.
R ¹² represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ¹³ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, and r Is an integer of 1 to 4, and when r is 2 or more, a plurality of R ¹² may be the same or different.
R ⁶ and R ⁷ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a hydroxyl group, m is an integer of 0 to 3, n is an integer of 0 to 4, m and n are independent of each other, and when m is 2 or more, a plurality of R ⁶ are the same or different. And when n is 2 or more, a plurality of R ⁷ may be the same or different. ) At least one of R ¹ and R ² is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, X is COOR ³ , and R ³ is- a _{^{(R 10 -O) q -R 11}} , amino hydroxybenzophenone derivative or salt thereof according to claim 1. At least one of R ¹ and R ² is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, and X is CONR ⁴ R ⁵ , wherein R ⁴ and The method for producing an aminohydroxybenzophenone derivative or a salt thereof according to claim 1, wherein at least one of R ⁵ is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group. A compound represented by the general formula (II) or a salt thereof;

(In the formula, indefinite items have the following meanings independently of each other.
Y represents fluorine, chlorine, bromine, iodine, or a sulfonic acid ester group such as a methanesulfonyl group, a p-toluenesulfonyl group, a nitrobenzenesulfonyl group, and a trifluoromethanesulfonyl group.
R ¹⁴ represents —O—R ¹⁵ , chlorine, bromine, or iodine, and R ¹⁵ represents a linear or branched alkyl group having 1 to 4 carbon atoms.
R ⁶ and R ⁷ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms or a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a hydroxyl group, m is an integer of 0 to 3, n is an integer of 0 to 4, m and n are independent of each other, and when m is 2 or more, a plurality of R ⁶ are the same or different. And when n is 2 or more, a plurality of R ⁷ may be the same or different. )
Reacting the compound represented by the general formula (III) or a salt thereof,

(In the formula, indefinite items have the following meanings independently of each other.
R ¹ and R ² each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ⁸ —O) _p —R ⁹ . (However, ^one of R ¹ or R ² may be a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), and NR ¹ R ² represents a 5- or 6-membered heterocycle. May be formed, the heterocycle is substituted with at least one hydroxyl group, and the heterocycle may be further substituted.
R ⁸ represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ⁹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, p Is an integer of 1 to 4, and when p is 2 or more, a plurality of R ⁸ may be the same or different. )
A process for producing an aminohydroxybenzophenonamide derivative represented by the general formula (IV) or a salt thereof.

Y is fluorine, chlorine, bromine, or iodine, R ¹⁴ represents —O—R ¹⁵ , R ¹⁵ is a linear or branched alkyl group having 1 to 4 carbon atoms, and R ¹ And at least one of R ² is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, The method for producing an aminohydroxybenzophenone amide derivative or a salt thereof according to claim 4 . An aminohydroxybenzophenone amide derivative represented by the general formula (IV) or a salt thereof;

(In the formula, indefinite items have the following meanings independently of each other.
R ¹ and R ² each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ⁸ —O) _p —R ⁹ . (However, ^one of R ¹ or R ² may be a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), and NR ¹ R ² represents a 5- or 6-membered heterocycle. May be formed, the heterocycle is substituted with at least one hydroxyl group, and the heterocycle may be further substituted.
R ⁸ represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ⁹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, p Is an integer of 1 to 4, and when p is 2 or more, a plurality of R ⁸ may be the same or different. )
Reacting with a compound represented by the general formula (V) or a salt thereof,

(In the formula, indefinite items have the following meanings independently of each other.
R ³ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, or — (R ¹⁰ —O) _q —R ¹¹ .
R ¹⁰ represents a linear or branched alkylene group having 1 to 4 carbon atoms, R ¹¹ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, q Is an integer of 1 to 4, and when q is 2 or more, a plurality of R ¹⁰ may be the same or different. )
A process for producing an aminohydroxybenzophenone ester derivative represented by the general formula (VI) or a salt thereof.

At least one of R ¹ and R ² is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with at least one hydroxyl group, and R ³ is — (R ¹⁰ —O) _q —R. ^The method for producing an aminohydroxybenzophenone ester derivative or a salt thereof according to claim 6, which is ¹¹ .   The ultraviolet absorber containing the aminohydroxybenzophenone derivative or its salt in any one of Claims 1-3. The skin external preparation containing the aminohydroxybenzophenone derivative or its salt in any one of Claims 1-3.